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{{Short description|Broad and loose category of small proteins important in cell signaling}}
'''Cytokines''' (Greek ''cyto-'', cell; and ''-kinos'', movement) are small [[cell (biology)|cell]]-signaling [[protein]] [[molecules]] that are secreted by numerous cells and are a category of [[signaling molecules]] used extensively in [[intercellular communication]]. Cytokines can be classified as [[proteins]], [[peptides]], or [[glycoproteins]]; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the [[body]] by cells of diverse embryological origin.<ref>{{cite book |author=Gilman A, Goodman LS, Hardman JG, Limbird LE |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2001 |isbn=0-07-135469-7}}</ref>
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Distinguish|text=[[Cytokinin]], a class of plant hormones promoting cell division}}
{{Use dmy dates|date=November 2017}}
[[File:Cytokine release.jpg|thumb|264x264px|3D [[medical animation]] still showing secretion of cytokines]]


'''Cytokines''' ({{IPAc-en|'|s|aɪ|t|ə|k|aɪ|n}})<ref>{{cite web |url= https://dictionary.cambridge.org/us/dictionary/english/cytokine|title= CYTOKINE|author=<!--Not stated--> |date= |website=dictionary.cambridge.org |publisher= |access-date= 2024-09-27 |quote=}} </ref> are a broad and loose category of small [[protein]]s (~5–25 [[kDa]]<ref>{{cite book|title=Janeway's Immunobiology|publisher=Garland Science|year=2017|isbn=978-0-8153-4551-0|pages=107|language=english}}</ref>) important in [[cell signaling]]. Due to their size, cytokines cannot cross the [[lipid bilayer]] of cells to enter the [[cytoplasm]] and therefore typically exert their functions by interacting with specific [[cytokine receptor|cytokine receptors]] on the target cell surface. Cytokines have been shown to be involved in [[autocrine signaling|autocrine]], [[paracrine signaling|paracrine]] and [[endocrine signaling]] as [[Immunomodulation|immunomodulating agents]].
The term "cytokine" has been used to refer to the [[immunomodulator|immunomodulating]] agents, such as [[interleukin]]s and [[interferon]]s. [[Biochemists]] disagree as to which molecules should be termed cytokines and which [[hormones]]. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10{{sup|-9}}) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10{{sup|-12}}) concentrations that can increase up to 1,000-fold during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident [[macrophage]]s (many near the interface with the external environment) are potent producers of [[Interleukin 1|IL-1]], [[Interleukin-6|IL-6]], and [[TNF-α]].<ref>Boyle, J. J. (2005). Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol, 3(1), 63-68. [http://www.ncbi.nlm.nih.gov/pubmed/15638783 PMID=15638783]</ref> In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the [[pancrea]]s).<ref name="Cannon2000">{{cite journal |author=Cannon JG |title=Inflammatory Cytokines in Nonpathological States |journal=News Physiol Sci. |year=2000 |volume=15 |pages=298–303 |pmid=11390930}}</ref> As of 2008, the current terminology refers to cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and hormones.


Cytokines include [[chemokine]]s, [[interferon]]s, [[interleukin]]s, [[lymphokine]]s, and [[tumour necrosis factor]]s, but generally not hormones or [[growth factor]]s (despite some [[growth factor#cytokine|overlap in the terminology]]){{Cn|date=May 2024|reason=Sources classify all sorts of growth factors as cytokines (CSFs, TGFs, I can see DOI:10.1159/000070922 argues NGFs are cytokines, etc), so it's not trivial to verify whether this is an exception ('generally not hormones or growth factors'). Terminology seems to vary and could use a source.}}. Cytokines are produced by a broad range of cells, including immune cells like [[macrophage]]s, [[B cell|B lymphocytes]], [[T cell|T lymphocytes]] and [[mast cell]]s, as well as [[Endothelium|endothelial cells]], [[fibroblast]]s, and various [[stromal cell]]s; a given cytokine may be produced by more than one type of cell.<ref>{{cite book |last1=Lackie |first1=John |chapter=Cytokines |chapter-url=https://www.oxfordreference.com/view/10.1093/acref/9780199549351.001.0001/acref-9780199549351-e-2315 |title=A Dictionary of Biomedicine |date=2010 |publisher=Oxford University Press |isbn=978-0-19-954935-1 }}</ref><ref>{{cite book |chapter=Cytokine |title=Stedman's Medical Dictionary |edition=28th |publisher=Wolters Kluwer Health, Lippincott Williams & Wilkins |year=2006 |isbn=978-0-7817-6450-6 }}</ref> They act through [[cell surface receptor]]s and are especially important in the [[immune system]]; cytokines modulate the balance between [[humoral immunity|humoral]] and [[cell-mediated immunity|cell-based]] immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. They are different from [[hormone]]s, which are also important cell signaling molecules. Hormones circulate in higher concentrations, and tend to be made by specific kinds of cells. Cytokines are important in health and disease, specifically in host [[immune response]]s to [[infection]], [[inflammation]], [[Major trauma|trauma]], [[sepsis]], [[cancer]], and reproduction.
Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. For instance, to use hormone terminology, the action of cytokines may be [[autocrine]] or [[paracrine]] in [[chemotaxis]] and [[endocrine]] as a [[fever#Pyrogens|pyrogen]]. Further, as molecules, cytokines are not limited to their immunomodulatory role. For instance, cytokines are also involved in several developmental processes during [[embryogenesis]]<ref>{{cite journal|title=Cytokine cross-talk between mother and the embryo/placenta|journal=Journal of Reproductive Immunology|date=October–November 2001|first=Shigeru|last=Saito|coauthors=|volume=52|issue=1–2|pages=15–33|doi=10.1016/S0165-0378(01)00112-7|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8W-445B4KX-3&_user=10&_coverDate=11%2F30%2F2001&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1271989808&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cdad0fbe5c489efea109a3025c282e44|format=|accessdate=2010-03-29|pmid=11600175 }}</ref><ref group="nb">Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)</ref><ref>{{cite journal|title=Expression of leukemia inhibitory factor and its receptor in preimplantation embryos|journal=Journal of Reproductive Biology|date=October 1999|first=Hsin-Fu|last=Chen M.D.|coauthors=Jin-Yuh Shew, Hong-Nerng Ho, Wei-Li Hsu, Yu-Shih Yang|volume=72|issue=4|pages=713–719|doi=10.1016/S0015-0282(99)00306-4|url=http://linkinghub.elsevier.com/retrieve/pii/S0015028299003064|format=|accessdate=2010-03-29 }}</ref><ref group="nb">Chen explains the regulatory activity of [[Leukemia inhibitory factor|LIF]] in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner."(719)</ref>


The word comes from the ancient [[Greek language]]: ''cyto'', from Greek κύτος, ''kytos'', 'cavity, cell' + ''kines'', from Greek κίνησις, ''kinēsis'', 'movement'.
== Discovery of Cytokines ==


== Discovery ==
[[Barry Bloom]] and [[John David]] independently discovered and characterized the activity of a soluble molecule released from [[lymphocytes]] that inhibited the random migration of [[macrophages]] (currently known as [[Macrophage migration inhibitory factor]]). They loaded macrophages from an unimmunized animal into a capillary tube, and then placed medium from either unstimulated lymphocytes or stimulated lymphocytes. They found that the medium from the stimulated lymphocytes prevented the random migration of macrophages out of the tube. This showed that there was a way for cell-cell communication that did not require cell-cell contact.


Interferon-alpha, an [[interferon type I]], was identified in 1957 as a protein that interfered with viral replication.<ref name="pmid13465720">{{cite journal | vauthors = Isaacs A, Lindenmann J | s2cid = 202574492 | title = Virus interference. I. The interferon | journal = Proc. R. Soc. Lond. B Biol. Sci. | volume = 147 | issue = 927 | pages = 258–267 | date = September 1957 | pmid = 13465720 | bibcode = 1957RSPSB.147..258I | doi = 10.1098/rspb.1957.0048 }}</ref> The activity of interferon-gamma (the sole member of the [[interferon type II]] class) was described in 1965; this was the first identified [[lymphocyte]]-derived mediator.<ref name="pmid17838106">{{cite journal | vauthors = Wheelock EF | s2cid = 1366348 | title = Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin | journal = Science | volume = 149 | issue = 3681 | pages = 310–311 | date = July 1965 | pmid = 17838106 | doi = 10.1126/science.149.3681.310 | bibcode = 1965Sci...149..310W }}</ref> [[Macrophage migration inhibitory factor]] (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.<ref name="pmid5938421">{{cite journal | vauthors = Bloom BR, Bennett B | s2cid = 43168526 | title = Mechanism of a reaction in vitro associated with delayed-type hypersensitivity | journal = Science | volume = 153 | issue = 3731 | pages = 80–82 | date = July 1966 | pmid = 5938421 | doi = 10.1126/science.153.3731.80 | bibcode = 1966Sci...153...80B }}</ref><ref name="pmid5229858">{{cite journal | vauthors = David JR | title = Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 56 | issue = 1 | pages = 72–77 | date = July 1966 | pmid = 5229858 | pmc = 285677 | doi = 10.1073/pnas.56.1.72 | bibcode = 1966PNAS...56...72D | doi-access = free }}</ref>
== Effects ==
Each cytokine has a matching [[Receptor (biochemistry)|cell-surface receptor]]. Subsequent [[biochemical cascade|cascades]] of intracellular signalling then alter cell functions. This may include the upregulation and/or downregulation of several [[genes]] and their [[transcription factors]], resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by [[enzyme inhibitor|feedback inhibition]].


In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines".<ref name="pmid5822903">{{cite journal | vauthors = Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT | s2cid = 4172811 | title = "Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation | journal = Nature | volume = 224 | issue = 5214 | pages = 38–42 | date = October 1969 | pmid = 5822903 | doi = 10.1038/224038a0 | bibcode = 1969Natur.224...38D }}</ref> In 1974, pathologist Stanley Cohen, M.D. (not to be confused with the [[Stanley Cohen (biochemist)|Nobel laureate]] named Stanley Cohen, who was a PhD biochemist; '''nor''' with the MD geneticist [[Stanley Norman Cohen]]) published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine.<ref name="pmid4156495">{{cite journal | vauthors = Cohen S, Bigazzi PE, Yoshida T | title = Commentary. Similarities of T cell function in cell-mediated immunity and antibody production | journal = Cell. Immunol. | volume = 12 | issue = 1 | pages = 150–159 | date = April 1974 | pmid = 4156495 | doi = 10.1016/0008-8749(74)90066-5 }}</ref> In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.<ref>{{cite journal|last=Ogawa|first=M|date=1993|title=Differentiation and proliferation of hematopoetic stem cells|journal=Blood|volume=81|issue=11|pages=2844–2853|doi=10.1182/blood.V81.11.2844.2844|pmid=8499622|doi-access=free}}</ref>
The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable "redundancy", in that many cytokines appear to share similar functions.


==Difference from hormones==
It seems to be a paradox that cytokines binding to [[antibody|antibodies]] have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.
Classic [[hormone]]s circulate in [[aqueous solution]] in nanomolar (10{{sup|-9}} M) [[molar concentration|concentrations]] that usually vary by less than one [[order of magnitude]]. In contrast, some cytokines (such as [[Interleukin-6|IL-6]]) circulate in picomolar (10{{sup|-12}} M) concentrations that can increase up to 1,000 times during [[injury|trauma]] or [[infection]]. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all [[nucleated]] cells, but especially endo/epithelial cells and resident [[macrophage]]s (many near the interface with the external environment) are potent producers of [[Interleukin 1|IL-1]], [[Interleukin-6|IL-6]], and [[TNF-α]].<ref>{{cite journal | vauthors = Boyle JJ | title = Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture | journal = Current Vascular Pharmacology | volume = 3 | issue = 1 | pages = 63–68 | date = January 2005 | pmid = 15638783 | doi = 10.2174/1570161052773861 | citeseerx = 10.1.1.324.9948 }}</ref> In contrast, classic hormones, such as [[insulin]], are secreted from discrete [[gland]]s such as the [[pancreas]].<ref name="Cannon2000">{{cite journal | vauthors = Cannon JG | title = Inflammatory Cytokines in Nonpathological States | journal = News in Physiological Sciences | volume = 15 | issue = 6 | pages = 298–303 | date = December 2000 | pmid = 11390930 | doi = 10.1152/physiologyonline.2000.15.6.298 }}</ref> The current terminology refers to cytokines as [[Immunotherapy|immunomodulating agents]].


A contributing factor to the difficulty of distinguishing cytokines from hormones is that some [[immunomodulation|immunomodulating]] effects of cytokines are systemic (''i.e.'', affecting the whole organism) rather than local. For instance, to accurately utilize hormone terminology, cytokines may be [[autocrine]] or [[paracrine]] in nature, and [[chemotaxis]], [[chemokinesis]] and [[endocrine]] as a [[fever#Pyrogens|pyrogen]]. Essentially, cytokines are not limited to their immunomodulatory status as molecules.
Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of <ref>Said EA, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010 Apr;16(4):452-9.</ref> T-cell expansion and function by up-regulating [[programmed cell death 1|PD-1]] levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.<ref>Elias A. Said ''et al.'' 2009, PD-1 Induced IL10 Production by Monocytes Impairs T-cell Activation in a Reversible Fashion" ''Nature Medicine'' 2010; 452-9.</ref>
[[File:Signal transduction pathways.svg|alt=A scalable vector graphic of signal transduction pathways|thumb|'''Cytokines''' typically activate second messenger systems, like JAK-STAT pathways, as illustrated on the left side of the diagram. Conversely, '''hormones''' typically activate different signaling pathways, like G protein-coupled receptors, seen at the top of the figure.]]

Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread [[papule|papular]] eruptions.<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. ISBN 0-7216-2921-0.</ref>


== Nomenclature ==
== Nomenclature ==
Cytokines have been classed as [[lymphokine]]s, [[interleukin]]s, and [[chemokine]]s, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy and [[Pleiotropy|pleiotropism]], such distinctions, allowing for exceptions, are obsolete.


* The term ''interleukin'' was initially used by researchers for those cytokines whose presumed targets are principally [[white blood cell]]s (leukocytes). It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by [[T-helper cell]]s.
Cytokines have been classed as [[lymphokines]], [[interleukins]], and [[chemokines]], based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and [[Pleiotropy|pleiotropism]], such distinctions, allowing for exceptions, are obsolete.
* ''Lymphokines'': produced by lymphocytes

* ''Monokines'': produced exclusively by [[monocytes]]
* The term ''interleukin'' was initially used by researchers for those cytokines whose presumed targets are principally [[White blood cell|leukocytes]]. It is now used largely for designation of newer cytokine molecules discovered every day and bears little relation to their presumed function. The vast majority of these are produced by [[T-helper cell]]s.
* ''Interferons'': involved in antiviral responses
* The term ''chemokine'' refers to a specific class of cytokines that mediates chemoattraction ([[chemotaxis]]) between cells.
* ''[[Colony stimulating factors]]'': support the growth of cells in semisolid media
* ''Chemokines'': mediate chemoattraction ([[chemotaxis]]) between cells.


== Classification ==
== Classification ==


=== Structural ===
=== Structural ===
Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:


*The four-[[Helix bundle|α-helix bundle]] family ({{InterPro|IPR009079}}): member cytokines have three-dimensional structures with a bundle of four [[alpha helix|α-helices]]. This family, in turn, is divided into three sub-families:
Structural homology has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:
# the [[interleukin 2|IL-2]] subfamily. This is the largest family. It contains several non-immunological cytokines including [[erythropoietin]] (EPO) and [[thrombopoietin]] (TPO).<ref>{{cite journal | vauthors = Leonard WJ | title = Cytokines and immunodeficiency diseases | journal = Nature Reviews. Immunology | volume = 1 | issue = 3 | pages = 200–208 | date = December 2001 | pmid = 11905829 | doi = 10.1038/35105066 | url = https://zenodo.org/record/1233113 | s2cid = 5466985 | doi-access = free }}</ref> They can be grouped into ''long-chain'' and ''short-chain'' cytokines by topology.<ref>{{cite journal | vauthors = Rozwarski DA, Gronenborn AM, Clore GM, Bazan JF, Bohm A, Wlodawer A, Hatada M, Karplus PA | title = Structural comparisons among the short-chain helical cytokines | journal = Structure | volume = 2 | issue = 3 | pages = 159–173 | date = March 1994 | pmid = 8069631 | doi = 10.1016/s0969-2126(00)00018-6 | doi-access = free }}</ref> Some members share the [[common gamma chain]] as part of their receptor.<ref>{{cite journal | vauthors = Reche PA | title = The tertiary structure of γc cytokines dictates receptor sharing | journal = Cytokine | volume = 116 | pages = 161–168 | date = April 2019 | pmid = 30716660 | doi = 10.1016/j.cyto.2019.01.007 | s2cid = 73449371 }}</ref>

# the [[interferon|interferon (IFN)]] subfamily.
*The four-[[Helix bundle|α-helix bundle]] family - Member cytokines have three-dimensional structures with four bundles of [[alpha helix|α-helices]]. This family, in turn, is divided into three sub-families:
*# the [[interleukin 2|IL-2]] subfamily
# the [[interleukin 10|IL-10]] subfamily.
*The [[interleukin 1|IL-1]] family, which primarily includes IL-1 and [[interleukin|IL-18]].
*# the [[interferon|interferon (IFN)]] subfamily
* The [[cysteine knot]] cytokines ({{UniProt|IPR029034}}) include members of the [[transforming growth factor beta superfamily]], including [[TGF beta 1|TGF-β1]], [[TGF beta 2|TGF-β2]] and [[TGF beta 3|TGF-β3]].
*# the [[interleukin 10|IL-10]] subfamily.
* The [[interleukin 17|IL-17]] family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that have cytotoxic effects.
**The first of these three, the IL-2 subfamily, is the largest. It contains several non-immunological cytokines including [[erythropoietin]] (EPO) and [[thrombopoietin]] (TPO). Furthermore, four-α-helix bundle cytokines can be grouped into ''long-chain'' and ''short-chain'' cytokines.{{citation needed|date=April 2012}}<!--citation needed for whole sub-bullet-->
*the [[interleukin 1|IL-1]] family, which primarily includes IL-1 and [[interleukin|IL-18]]
*the [[interleukin 17|IL-17]] family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.


=== Functional ===
=== Functional ===
A classification that proves more useful in clinical and experimental practice outside of [[structural biology]] divides immunological cytokines into those that enhance [[cellular immune response]]s, type 1 (TNFα, IFN-γ, etc.), and those that enhance [[antibody]] responses, type 2 (TGF-β, [[interleukin 4|IL-4]], IL-10, [[interleukin 13|IL-13]], etc.). A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the [[pathogenesis]] of [[autoimmune disorder]]s. Several [[inflammatory cytokine]]s are induced by [[oxidative stress]].<ref name="pmid10477716">{{cite journal | vauthors = Vlahopoulos S, Boldogh I, Casola A, Brasier AR | title = Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation | journal = Blood | volume = 94 | issue = 6 | pages = 1878–1879 | date = September 1999 | pmid = 10477716 | doi = 10.1182/blood.V94.6.1878.418k03_1878_1889 | s2cid = 25974629 }}</ref><ref name="pmid17461946">{{cite journal | vauthors = David F, Farley J, Huang H, Lavoie JP, Laverty S | title = Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes | journal = Vet Surg | volume = 36 | issue = 3 | pages = 221–227 | date = April 2007 | pmid = 17461946 | doi = 10.1111/j.1532-950X.2007.00253.x }}</ref> The fact that cytokines themselves trigger the release of other cytokines <ref name="pmid24185478">{{cite journal | vauthors = Chokkalingam V, Tel J, Wimmers F, Liu X, Semenov S, Thiele J, Figdor CG, Huck WT | title = Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics | journal = Lab Chip | volume = 13 | issue = 24 | pages = 4740–4744 | date = December 2013 | pmid = 24185478 | doi = 10.1039/c3lc50945a | url = http://repository.tue.nl/855231 | access-date = 21 November 2020 | archive-date = 29 November 2020 | archive-url = https://web.archive.org/web/20201129095235/http://repository.tue.nl/855231 | url-status = dead }}</ref><ref name="pmid11922866">{{cite journal | vauthors = Carpenter LR, Moy JN, Roebuck KA | title = Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1 | journal = BMC Infect. Dis. | volume = 2 | pages = 5 | date = March 2002 | pmid = 11922866 | pmc = 102322 | doi = 10.1186/1471-2334-2-5 | doi-access = free }}</ref><ref name="pmid16191192">{{cite journal | vauthors = Tian B, Nowak DE, Brasier AR | title = A TNF-induced gene expression program under oscillatory NF-kappaB control | journal = BMC Genomics | volume = 6 | pages = 137 | date = September 2005 | pmid = 16191192 | pmc = 1262712 | doi = 10.1186/1471-2164-6-137 | doi-access = free }}</ref> and also lead to increased oxidative stress makes them important in chronic [[inflammation]], as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.<ref name="pmid17426506">{{cite journal | vauthors = Zhang JM, An J | title = Cytokines, inflammation, and pain | journal = Int Anesthesiol Clin | volume = 45 | issue = 2 | pages = 27–37 | date = 2007 | pmid = 17426506 | pmc = 2785020 | doi = 10.1097/AIA.0b013e318034194e }}</ref> There are both pro-inflammatory and [[anti-inflammatory]] cytokines that regulate this{{Clarify|reason=Which pathway?|date=July 2024}} pathway.
A classification that proves more useful in clinical and experimental practice divides immunological cytokines into those that enhance [[cellular immune response]]s, type 1 (IFN-γ, TGF-β, etc.), and type 2 ([[interleukin 4|IL-4]], [[interleukin 10|IL-10]], [[interleukin 13|IL-13]], etc.), which favor [[antibody response]]s.

A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the [[pathogenesis]] of [[autoimmune disorder]]s.

Several inflammatory cytokines are induced by [[Oxidative stress|oxidant stress]].<ref>{{cite journal | pmid = 10477716 | year = 1999 | last1 = Vlahopoulos | first1 = S | last2 = Boldogh | first2 = I | last3 = Casola | first3 = A | last4 = Brasier | first4 = AR | title = Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation | volume = 94 | issue = 6 | pages = 1878–89 | journal = Blood }}</ref><ref>{{cite journal | pmid = 17461946 | year = 2007 | last1 = David | first1 = F | last2 = Farley | first2 = J | last3 = Huang | first3 = H | last4 = Lavoie | first4 = JP | last5 = Laverty | first5 = S | title = Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes | volume = 36 | issue = 3 | pages = 221–7 | doi = 10.1111/j.1532-950X.2007.00253.x | journal = Veterinary surgery : VS }}</ref> The fact that cytokines themselves trigger the release of other cytokines<ref>{{cite journal | pmid = 11922866 | year = 2002 | last1 = Carpenter | first1 = LR | last2 = Moy | first2 = JN | last3 = Roebuck | first3 = KA | title = Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1 | volume = 2 | pages = 5 | pmc = 102322 | journal = BMC infectious diseases }}</ref><ref>{{cite journal | pmid = 16191192 | year = 2005 | last1 = Tian | first1 = B | last2 = Nowak | first2 = DE | last3 = Brasier | first3 = AR | title = A TNF-induced gene expression program under oscillatory NF-kappaB control | volume = 6 | pages = 137 | doi = 10.1186/1471-2164-6-137 | pmc = 1262712 | journal = BMC Genomics }}</ref> and also lead to increased oxidant stress makes them important in chronic [[inflammation]], as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, INF-a).


== Receptors ==
== Receptors ==
{{Main|Cytokine receptor}}
{{Main|Cytokine receptor}}
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleiomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.


A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.
A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.


* [[Immunoglobulin superfamily|Immunoglobulin (Ig) superfamily]], which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural [[homology (biology)|homology]] with immunoglobulins ([[antibody|antibodies]]), [[cell adhesion molecule]]s, and even some cytokines. Examples: IL-1 receptor types.
* [[Immunoglobulin superfamily|Immunoglobulin (Ig) superfamily]], which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share [[structural homology]] with immunoglobulins ([[antibody|antibodies]]), [[cell adhesion molecule]]s, and even some cytokines. Examples: IL-1 receptor types.
* Hemopoietic [[Growth Factor]] (type 1) family, whose members have certain conserved motifs in their extracellular [[amino-acid]] domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of [[Severe Combined Immunodeficiency]] ([[X-SCID]]).
* [[Hemopoietic growth factor|Hemopoietic Growth Factor]] (type 1) family, whose members have certain conserved motifs in their extracellular [[amino-acid]] domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of [[Severe Combined Immunodeficiency]] ([[X-SCID]]).
* [[Interferon]] (type 2) family, whose members are receptors for IFN β and γ.
* Interferon (type 2) family, whose members are receptors for IFN β and γ.
* [[Tumor necrosis factors]] (TNF) (type 3) family, whose members share a [[cysteine]]-rich common extracellular binding domain, and includes several other non-cytokine [[ligands]] like [[CD40]], [[CD27]] and [[CD30]], besides the ligands on which the family is named (TNF).
* [[Tumor necrosis factor]]s (TNF) (type 3) family, whose members share a [[cysteine]]-rich common extracellular binding domain, and includes several other non-cytokine [[ligands]] like [[CD40]], [[CD27]] and [[CD30]], besides the ligands on which the family is named.
* [[7TM Receptor|Seven transmembrane helix]] family, the ubiquitous receptor type of the animal kingdom. All [[G protein-coupled receptors]] (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for [[HIV]] ([[CD4]] and [[CCR5]]), also belong to this family.{{Citation needed|date=January 2011}}
* [[7TM Receptor|Seven transmembrane helix]] family, the ubiquitous receptor type of the animal kingdom. All [[G protein-coupled receptors]] (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for [[HIV]] ([[CD4]] and [[CCR5]]), also belong to this family.{{Citation needed|date=January 2011}}
* [[Interleukin-17 receptor]] (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.<ref>{{cite journal|last=Gaffen|first=Sarah|title=Structure and signalling in the IL-17 receptor superfamily|journal=Nature Reviews Immunology|year=2009|month=August|volume=9|pages=556–567}}</ref>
* [[Interleukin-17 receptor]] (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.<ref name="pmid19575028">{{cite journal | vauthors = Gaffen SL | title = Structure and signalling in the IL-17 receptor family | journal = Nat. Rev. Immunol. | volume = 9 | issue = 8 | pages = 556–567 | date = August 2009 | pmid = 19575028 | pmc = 2821718 | doi = 10.1038/nri2586 }}</ref>
*[[Interleukin-12]] (IL-12),secreted by Macrophage and act on THo (t-helper cell 0) and convert into TH1 (t-helper cell 1)which produce γ-IF.γ-IF activates Macrophage into super active cell which start cell mediated response.


== Disease ==
== Cellular effects ==
Each cytokine has a matching [[cell-surface receptor]]. Subsequent [[biochemical cascade|cascades]] of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several [[genes]] and their [[transcription factors]], resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by [[enzyme inhibitor|feedback inhibition]]. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to [[antibody|antibodies]] have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.


It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of<ref name="Said2010">{{cite journal | vauthors = Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP | title = Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 452–459 | date = April 2010 | pmid = 20208540 | pmc = 4229134 | doi = 10.1038/nm.2106 }}</ref> T-cell expansion and function by up-regulating [[programmed cell death 1|PD-1]] levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.<ref name="Said2010" /> Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread [[papule|papular eruptions]].<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. {{ISBN|0-7216-2921-0}}.{{page needed|date=July 2013}}</ref>
Adverse effects of cytokines have been linked to many disease states and conditions ranging from [[major depression]]<ref name="pmid20015486">{{cite journal | author = Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL | title = A meta-analysis of cytokines in major depression | journal = Biol Psychiatry | volume = 67 | issue = 5 | pages = 446–457 | year = 2010 | pmid = 20015486 | doi=10.1016/j.biopsych.2009.09.033}}</ref> and [[Alzheimer's disease]]<ref name="pmid20692646">{{cite journal | author = Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N | title = A meta-analysis of cytokines in Alzheimer's disease | journal = Biol Psychiatry | volume = 68 | issue = 10 | pages = 930–941 | year = 2010 | pmid = 20692646 | doi=10.1016/j.biopsych.2010.06.012}}</ref> to [[cancer]]<ref name="pmid11239407">{{cite journal | author = Locksley RM, Killeen N, Lenardo MJ | title = The TNF and TNF receptor superfamilies: integrating mammalian biology | journal = Cell | volume = 104 | issue = 4 | pages = 487–501 | year = 2001 | pmid = 11239407 | doi = 10.1016/S0092-8674(01)00237-9 }}</ref> with levels either being elevated or changed. Over-secretion of cytokines can trigger a dangerous syndrome known as a [[cytokine storm]]; this may have been the cause of severe adverse events during a clinical trial of [[TGN1412]]. Cytokine storms also were the main cause of death in the [[1918 flu pandemic|1918 "Spanish Flu"]] pandemic. Deaths were weighted more heavily towards people with healthy immune systems, due to its ability to produce stronger immune responses, like increasing cytokine levels. Another important<ref>{{cite journal|last=Makhija|first=Rohit|coauthors=Kingsnorth|journal=Journal of HBP surgery|year=2002|volume=9|pages=401–410}}</ref> example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade resulting in the systemic inflammatory response syndrome and multi organ failure associated with this intra-abdominal catastrophe.


==Roles in health and disease==
=== Plasma levels ===
Cytokines are involved in several developmental processes during [[embryonic development]].<ref name="pmid11600175">{{cite journal | vauthors = Saito S | title = Cytokine cross-talk between mother and the embryo/placenta | journal = J. Reprod. Immunol. | volume = 52 | issue = 1–2 | pages = 15–33 | date = 2001 | pmid = 11600175 | doi = 10.1016/S0165-0378(01)00112-7}}</ref><ref group="nb">Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)</ref><ref name="pmid10521116">{{cite journal | vauthors = Chen HF, Shew JY, Ho HN, Hsu WL, Yang YS | title = Expression of leukemia inhibitory factor and its receptor in preimplantation embryos | journal = Fertil. Steril. | volume = 72 | issue = 4 | pages = 713–719 | date = October 1999 | pmid = 10521116 | doi = 10.1016/S0015-0282(99)00306-4 | doi-access = free }}</ref><ref group="nb">Chen explains the regulatory activity of [[Leukemia inhibitory factor|LIF]] in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner." (719)</ref> Cytokines are released from the [[blastocyst]], and are also expressed in the [[endometrium]], and have critical roles in the stages of [[zona hatching]], and [[implantation (embryology)|implantation]].<ref name="Seshagiri">{{cite journal |last1=Seshagiri |first1=Polani B. |last2=Vani |first2=Venkatappa |last3=Madhulika |first3=Pathak |title=Cytokines and Blastocyst Hatching |journal=American Journal of Reproductive Immunology |pages=208–217 |language=en |doi=10.1111/aji.12464 |date=March 2016|volume=75 |issue=3 |pmid=26706391 |s2cid=11540123 |doi-access=free }}</ref> Cytokines are crucial for fighting off infections and in other immune responses.<ref name="pmid10936147">{{cite journal | vauthors = Dinarello CA | title = Proinflammatory cytokines | journal = Chest | volume = 118 | issue = 2 | pages = 503–508 | date = August 2000 | pmid = 10936147 | doi = 10.1378/chest.118.2.503 }}</ref> However, they can become dysregulated and pathological in [[inflammation]], trauma, [[sepsis]],<ref name="pmid10936147" /> and [[hemorrhagic stroke]].<ref>{{cite journal | vauthors = Zhu H, Wang Z, Yu J, et al. | s2cid = 85495400 | title = Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage | journal = Prog. Neurobiol. | volume = 178 | pages = 101610 | date = March 2019 | pmid = 30923023 | doi = 10.1016/j.pneurobio.2019.03.003 }}</ref> Dysregulated cytokine secretion in the aged population can lead to [[inflammaging]], and render these individuals more vulnerable to age-related diseases like neurodegenerative diseases and type 2 diabetes.<ref>{{cite journal |last1=Franceschi |first1=C. |last2=Bonafè |first2=M. |last3=Valensin |first3=S. |last4=Olivieri |first4=F. |last5=De Luca |first5=M. |last6=Ottaviani |first6=E. |last7=De Benedictis |first7=G. |date=June 2000 |title=Inflamm-aging. An evolutionary perspective on immunosenescence |journal=Annals of the New York Academy of Sciences |volume=908 |issue=1 |pages=244–254 |doi=10.1111/j.1749-6632.2000.tb06651.x|issn=0077-8923 |pmid=10911963 |bibcode=2000NYASA.908..244F |s2cid=1843716}}</ref>


A 2019 review was inconclusive as to whether cytokines play any definitive role in [[ME/CFS]].<ref>{{Cite journal|title=A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)|first1=Matthew|last1=Corbitt|first2=Natalie|last2=Eaton-Fitch|first3=Donald|last3=Staines|first4=Hélène|last4=Cabanas|first5=Sonya|last5=Marshall-Gradisnik|date=24 August 2019|journal=BMC Neurology|volume=19|issue=1|pages=207|doi=10.1186/s12883-019-1433-0|doi-access=free |pmid=31445522|pmc=6708220}}</ref>
Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as [[rheumatoid arthritis]],<ref>Kokkonen, H. Arthritis & Rheumatism, Feb. 2, 2010; vol 62: pp 383–391</ref> as well as immunomodulatory effects of foods or drugs.<ref>{{cite journal |author=Nikolaeva LG, Maystat TV, Masyuk LA, Pylypchuk VS, Volyanskii YL, Kutsyna GA |title=Changes in CD4+ T-cells and HIV RNA resulting from combination of anti-TB therapy with Dzherelo in TB/HIV dually infected patients |journal=Drug Des Devel Ther |volume=2 |issue= |pages=87–93 |year=2009 |pmid=19920896 |pmc=2761183 |doi= |url=}}</ref> In addition, elevated levels of [[Interleukin-7|IL-7]], an important cytokine involved in T cell homeostasis, have been detected in the plasma of [[HIV|HIV-infected patients]].<ref>{{cite journal |author=Napolitano LA, Grant RM, Deeks SG, ''et al.'' |title=Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis |journal=Nat. Med. |volume=7 |issue=1 |pages=73–9 |year=2001 |month=January |pmid=11135619 |doi=10.1038/83381 |url=}}</ref>


A 2024 study found a positive correlation between plasma interleukin [[interleukin 2|IL-2]] and fatigue in patients with type 1 [[narcolepsy]].<ref>{{Cite journal|title=Association between cytokines and fatigue in patients with type 1 narcolepsy |first1=Qiao|last1=Yang|first2=Qiong|last2=Wu|first3=Qinqin|last3=Zhan|first4=Liying|last4=Deng|first5=Yongmin|last5=Ding|first6=Fen|last6=Wang|first7=Jin|last7=Chen|first8=Liang|last8=Xie|date=February 2024|journal=Journal of Clinical Neuroscience|volume=120|issue=1|pages=102|doi=10.1016/j.jocn.2024.01.007|doi-access= |pmid= |pmc= }}</ref>
== Cysteine-knot cytokines ==
{{Expand section|date=February 2007}}


==Adverse effects==
Members of the [[transforming growth factor beta superfamily]] belong to this group, including [[TGF beta 1|TGF-β1]], [[TGF beta 2|TGF-β2]] and [[TGF beta 3|TGF-β3]].


Adverse effects of cytokines have been linked to many disease states and conditions ranging from [[schizophrenia]], [[major depression]]<ref name="pmid20015486">{{cite journal | vauthors = Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL | s2cid = 230209 | title = A meta-analysis of cytokines in major depression | journal = Biol. Psychiatry | volume = 67 | issue = 5 | pages = 446–457 | date = March 2010 | pmid = 20015486 | doi = 10.1016/j.biopsych.2009.09.033 }}</ref> and [[Alzheimer's disease]]<ref name="pmid20692646">{{cite journal | vauthors = Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N | s2cid = 6544784 | title = A meta-analysis of cytokines in Alzheimer's disease | journal = Biol. Psychiatry | volume = 68 | issue = 10 | pages = 930–941 | date = November 2010 | pmid = 20692646 | doi = 10.1016/j.biopsych.2010.06.012 }}</ref> to [[cancer]].<ref name="pmid11239407">{{cite journal | vauthors = Locksley RM, Killeen N, Lenardo MJ | s2cid = 7657797 | title = The TNF and TNF receptor superfamilies: integrating mammalian biology | journal = Cell | volume = 104 | issue = 4 | pages = 487–501 | date = February 2001 | pmid = 11239407 | doi = 10.1016/S0092-8674(01)00237-9 | doi-access = free }}</ref> T regulatory cells ([[Tregs]]) and related-cytokines are effectively engaged in the process of tumor immune escape and functionally inhibit immune response against the tumor. Forkhead box protein 3 ([[Foxp3]]) as a transcription factor is an essential molecular marker of [[Treg]] cells. [[Foxp3]] polymorphism (rs3761548) might be involved in cancer progression like [[gastric cancer]] through influencing [[Tregs]] function and the secretion of immunomodulatory cytokines such as [[Interleukin 10|IL-10]], [[IL-35]], and [[TGF-β]].<ref>{{cite journal | vauthors = Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A | title = Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients | journal = Cytokine | volume = 138 | issue = | pages = 155351 | date = February 2021 | pmid = 33127257 | doi = 10.1016/j.cyto.2020.155351 | s2cid = 226218796 | url = https://www.sciencedirect.com/science/article/pii/S1043466620303677| issn =1043-4666 }}</ref>
== See also ==
Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by [[Cell adhesion molecule|adhesion molecules]] and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity.<ref name="pmid26119834">{{cite journal | vauthors = Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, Adamaki M, Bacopoulou F, Copland JA, Boldogh I, Karin M, Chrousos GP | title = Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment | journal = Cytokine Growth Factor Rev. | volume = 26 | issue = 4 | pages = 389–403 | date = August 2015 | pmid = 26119834 | pmc = 4526340 | doi = 10.1016/j.cytogfr.2015.06.001 }}</ref>
* [[Active Hexose Correlated Compound]]
* [[Adipokine]]s
* [[Apoptosis]]
* [[Secretion assay|Cytokine secretion assay]]
* [[Chemokine]]
* [[Cytokine storm]]
* [[ELISA]] assays
* [[ELISPOT]] assays
* [[FluoroSpot]] assays
* [[Granulocyte-colony stimulating factor]]
* [[Interleukin-7]]
* [[Lymphokine]]
* [[Signal transduction]]
* [[TSLP]]


Over-secretion of cytokines can trigger a dangerous [[cytokine storm syndrome]]. Cytokine storms may have been the cause of severe adverse events during a clinical trial of [[TGN1412]]. Cytokine storms are also suspected to have been the main cause of death in the [[1918 flu pandemic|1918 "Spanish Flu" pandemic]]. Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels. Another example of cytokine storm is seen in [[acute pancreatitis]]. Cytokines are integral and implicated in all angles of the cascade, resulting in the [[systemic inflammatory response syndrome]] and [[Multi organ dysfunction|multi-organ failure]] associated with this intra-abdominal catastrophe.<ref name="pmid12483260">{{cite journal |vauthors=Makhija R, Kingsnorth AN |title=Cytokine storm in acute pancreatitis |journal=Journal of Hepato-Biliary-Pancreatic Surgery |volume=9 |issue=4 |pages=401–410 |date=2002 |pmid=12483260 |doi=10.1007/s005340200049}}</ref> In the [[COVID-19 pandemic]], some deaths from [[Coronavirus disease 2019|COVID-19]] have been attributable to cytokine release storms.<ref name="covid-1">{{cite web|last1=Cron |first1=Randy |last2=Chatham |first2=W. Winn |url=https://www.vox.com/2020/3/12/21176783/coronavirus-covid-19-deaths-china-treatment-cytokine-storm-syndrome |title=How doctors can potentially significantly reduce the number of deaths from Covid-19| publisher=[[Vox (website)|Vox]] |access-date=14 March 2020|date=12 March 2020}}</ref><ref name="covid-2">{{cite journal |vauthors=Ruan Q, Yang K, Wang W, Jiang L, Song J |title=Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China |journal=Intensive Care Medicine |volume=46 |issue=5 |pages=846–848 |date=May 2020 |pmid=32125452 |pmc=7080116 |doi=10.1007/s00134-020-05991-x}}</ref><ref name="covid-3">{{cite journal |vauthors=Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ |title=COVID-19: consider cytokine storm syndromes and immunosuppression |journal=Lancet |volume=395 |issue=10229 |pages=1033–1034 |date=March 2020 |pmid=32192578 |pmc=7270045 |doi=10.1016/S0140-6736(20)30628-0}}</ref> Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in [[Coronavirus disease 2019|COVID-19]] infections.<ref>{{cite book |vauthors=Cascella M, Rajnik M, Cuomo A |display-authors=et al |title=Features, Evaluation, and Treatment of Coronavirus |publisher=StatPearls Publishing |url=https://www.ncbi.nlm.nih.gov/books/NBK554776 |access-date=4 December 2020|date=4 October 2020 |pmid=32150360}}</ref>
== Notes ==
{{Commons category|Cytokines}}
<references group="nb" />


==Medical use as drugs==
== References ==
{{reflist|2}}


Some cytokines have been developed into [[Biologic medical product|protein therapeutics]] using [[recombinant DNA]] technology.<ref>{{cite journal |vauthors=De Root AS, Scott DW |title=Immunogenicity of protein therapeutics |journal=Trends in Immunology |volume=28 |issue=11 |pages=482–490 |date=November 2007 |pmid=17964218 |doi=10.1016/j.it.2007.07.011}}</ref> Recombinant cytokines being used as drugs as of 2014 include:<ref>{{cite book |vauthors=Dimitrov DS |chapter=Therapeutic Proteins |title=Methods in Molecular Biology |volume=899 |pages=1–26 |year=2012 |pmid=22735943 |pmc=6988726 |doi=10.1007/978-1-61779-921-1_1 |isbn=978-1-61779-920-4}}</ref>
== External links ==
* [[Bone morphogenetic protein]] (BMP), used to treat bone-related conditions
* [https://www.immport.org/immportWeb/queryref/geneListSummary.do Cytokine Gene Summary, Ontology, Pathways and More - Immunology Database and Analysis Portal (ImmPort)]
* [[Erythropoietin]] (EPO), used to treat [[anemia]]
* [http://microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html Cytokine Tutorial]. dead link.
* [[Granulocyte colony-stimulating factor]] (G-CSF), used to treat [[neutropenia]] in cancer patients
* [http://www-immuno.path.cam.ac.uk/~immuno/part1/lec09/lec10_99.html Cell Interactions: Cytokines]. inactive link
* [[Granulocyte macrophage colony-stimulating factor]] (GM-CSF), used to treat [[neutropenia]] and [[fungal infections]] in cancer patients
* [http://www.emedicine.com/neuro/topic602.htm Reperfusion Injury in Stroke].
* [[Interferon alfa]], used to treat [[hepatitis C]] and [[multiple sclerosis]]
* [http://www.copewithcytokines.de CopeWithCytoKines Cytokines Online Pathfinder Encyclopaedia]
* [[Interferon beta]], used to treat [[multiple sclerosis]]

* [[Interleukin 2]] (IL-2), used to treat cancer.
{{Cell signaling}}
* [[Interleukin 11]] (IL-11), used to treat [[thrombocytopenia]] in cancer patients.
{{Immune system}}
* [[Interferon gamma]] is used to treat [[chronic granulomatous disease]]<ref name="pmid1312372">{{cite journal | vauthors = Woodman RC, Erickson RW, Rae J, Jaffe HS, Curnutte JT | title = Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity | journal = Blood | volume = 79 | issue = 6 | pages = 1558–1562 | date = March 1992 | pmid = 1312372 | doi = 10.1182/blood.v79.6.1558.bloodjournal7961558 | doi-access = free }}</ref> and [[osteopetrosis]]<ref name="pmid7753137">{{cite journal | vauthors = Key LL, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, Cure JK, Griffin PP, Ries WL | title = Long-term treatment of osteopetrosis with recombinant human interferon gamma | journal = N. Engl. J. Med. | volume = 332 | issue = 24 | pages = 1594–1599 | date = June 1995 | pmid = 7753137 | doi = 10.1056/NEJM199506153322402 | doi-access = free }}</ref>
{{Intercellular signaling peptides and proteins}}
{{Cytokines}}

[[Category:Cytokines|Cytokines]]'''Cytokines''' (Greek ''cyto-'', cell; and ''-kinos'', movement) are small [[cell (biology)|cell]]-signaling [[protein]] [[molecules]] that are secreted by numerous cells and are a category of [[signaling molecules]] used extensively in [[intercellular communication]]. Cytokines can be classified as [[proteins]], [[peptides]], or [[glycoproteins]]; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the [[body]] by cells of diverse embryological origin.<ref>{{cite book |author=Gilman A, Goodman LS, Hardman JG, Limbird LE |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2001 |isbn=0-07-135469-7}}</ref>

The term "cytokine" has been used to refer to the [[immunomodulator|immunomodulating]] agents, such as [[interleukin]]s and [[interferon]]s. [[Biochemists]] disagree as to which molecules should be termed cytokines and which [[hormones]]. As we learn more about each, anatomic and structural distinctions between the two are fading. Classic protein hormones circulate in nanomolar (10{{sup|-9}}) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10{{sup|-12}}) concentrations that can increase up to 1,000-fold during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident [[macrophage]]s (many near the interface with the external environment) are potent producers of [[Interleukin 1|IL-1]], [[Interleukin-6|IL-6]], and [[TNF-α]].<ref>Boyle, J. J. (2005). Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol, 3(1), 63-68. [http://www.ncbi.nlm.nih.gov/pubmed/15638783 PMID=15638783]</ref> In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the [[pancrea]]s).<ref name="Cannon2000">{{cite journal |author=Cannon JG |title=Inflammatory Cytokines in Nonpathological States |journal=News Physiol Sci. |year=2000 |volume=15 |pages=298–303 |pmid=11390930}}</ref> As of 2008, the current terminology refers to cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and hormones.

Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. For instance, to use hormone terminology, the action of cytokines may be [[autocrine]] or [[paracrine]] in [[chemotaxis]] and [[endocrine]] as a [[fever#Pyrogens|pyrogen]]. Further, as molecules, cytokines are not limited to their immunomodulatory role. For instance, cytokines are also involved in several developmental processes during [[embryogenesis]]<ref>{{cite journal|title=Cytokine cross-talk between mother and the embryo/placenta|journal=Journal of Reproductive Immunology|date=October–November 2001|first=Shigeru|last=Saito|coauthors=|volume=52|issue=1–2|pages=15–33|doi=10.1016/S0165-0378(01)00112-7|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T8W-445B4KX-3&_user=10&_coverDate=11%2F30%2F2001&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1271989808&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cdad0fbe5c489efea109a3025c282e44|format=|accessdate=2010-03-29|pmid=11600175 }}</ref><ref group="nb">Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)</ref><ref>{{cite journal|title=Expression of leukemia inhibitory factor and its receptor in preimplantation embryos|journal=Journal of Reproductive Biology|date=October 1999|first=Hsin-Fu|last=Chen M.D.|coauthors=Jin-Yuh Shew, Hong-Nerng Ho, Wei-Li Hsu, Yu-Shih Yang|volume=72|issue=4|pages=713–719|doi=10.1016/S0015-0282(99)00306-4|url=http://linkinghub.elsevier.com/retrieve/pii/S0015028299003064|format=|accessdate=2010-03-29 }}</ref><ref group="nb">Chen explains the regulatory activity of [[Leukemia inhibitory factor|LIF]] in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner."(719)</ref>thfgohdfobglhjbgljdflkgjkl

== Classification ==

=== Structural ===

Structural homology has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:

*The four-[[Helix bundle|α-helix bundle]] family - Member cytokines have three-dimensional structures with four bundles of [[alpha helix|α-helices]]. This family, in turn, is divided into three sub-families:
*# the [[interleukin 2|IL-2]] subfamily
*# the [[interferon|interferon (IFN)]] subfamily
*# the [[interleukin 10|IL-10]] subfamily.
**The first of these three, the IL-2 subfamily, is the largest. It contains several non-immunological cytokines including [[erythropoietin]] (EPO) and [[thrombopoietin]] (TPO). Furthermore, four-α-helix bundle cytokines can be grouped into ''long-chain'' and ''short-chain'' cytokines.{{citation needed|date=April 2012}}<!--citation needed for whole sub-bullet-->
*the [[interleukin 1|IL-1]] family, which primarily includes IL-1 and [[interleukin|IL-18]]
*the [[interleukin 17|IL-17]] family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.

=== Functional ===
A classification that proves more useful in clinical and experimental practice divides immunological cytokines into those that enhance [[cellular immune response]]s, type 1 (IFN-γ, TGF-β, etc.), and type 2 ([[interleukin 4|IL-4]], [[interleukin 10|IL-10]], [[interleukin 13|IL-13]], etc.), which favor [[antibody response]]s.

A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the [[pathogenesis]] of [[autoimmune disorder]]s.

Several inflammatory cytokines are induced by [[Oxidative stress|oxidant stress]].<ref>{{cite journal | pmid = 10477716 | year = 1999 | last1 = Vlahopoulos | first1 = S | last2 = Boldogh | first2 = I | last3 = Casola | first3 = A | last4 = Brasier | first4 = AR | title = Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation | volume = 94 | issue = 6 | pages = 1878–89 | journal = Blood }}</ref><ref>{{cite journal | pmid = 17461946 | year = 2007 | last1 = David | first1 = F | last2 = Farley | first2 = J | last3 = Huang | first3 = H | last4 = Lavoie | first4 = JP | last5 = Laverty | first5 = S | title = Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes | volume = 36 | issue = 3 | pages = 221–7 | doi = 10.1111/j.1532-950X.2007.00253.x | journal = Veterinary surgery : VS }}</ref> The fact that cytokines themselves trigger the release of other cytokines<ref>{{cite journal | pmid = 11922866 | year = 2002 | last1 = Carpenter | first1 = LR | last2 = Moy | first2 = JN | last3 = Roebuck | first3 = KA | title = Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1 | volume = 2 | pages = 5 | pmc = 102322 | journal = BMC infectious diseases }}</ref><ref>{{cite journal | pmid = 16191192 | year = 2005 | last1 = Tian | first1 = B | last2 = Nowak | first2 = DE | last3 = Brasier | first3 = AR | title = A TNF-induced gene expression program under oscillatory NF-kappaB control | volume = 6 | pages = 137 | doi = 10.1186/1471-2164-6-137 | pmc = 1262712 | journal = BMC Genomics }}</ref> and also lead to increased oxidant stress makes them important in chronic [[inflammation]], as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, INF-a).


== See also ==
== See also ==
{{Div col}}
* [[Active Hexose Correlated Compound]]
* [[Adipokine]]s
*[[Adipokine]]s
* [[Apoptosis]]
*[[Apoptosis]]
* [[Secretion assay|Cytokine secretion assay]]
*[[Cytokine redundancy]]
*[[Cytokine release syndrome]]
* [[Chemokine]]
* [[Cytokine storm]]
*[[Secretion assay|Cytokine secretion assay]]
* [[ELISA]] assays
*[[ELISA]] assays
* [[ELISPOT]] assays
*[[Myokine]]
*[[Signal transduction]]
* [[FluoroSpot]] assays
*[[Thymic stromal lymphopoietin]]
* [[Granulocyte-colony stimulating factor]]
* [[Interleukin-7]]
*[[Virokine]]
{{Div col end}}
* [[Lymphokine]]
* [[Signal transduction]]
* [[TSLP]]


== Notes ==
== Notes ==
{{Commons category|Cytokines}}
<references group="nb" />
<references group="nb" />


== References ==
== References ==
{{reflist|2}}
{{reflist|30em}}


== External links ==
==External links==
{{Commons category|Cytokines}}
* [https://www.immport.org/immportWeb/queryref/geneListSummary.do Cytokine Gene Summary, Ontology, Pathways and More - Immunology Database and Analysis Portal (ImmPort)]
*[http://www.cytokinesignalling.com Cytokine Signalling Forum]
* [http://microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html Cytokine Tutorial]. dead link.
*[http://www.elisakits.co.uk/immunology-cytokines/cytokine-tutorial Cytokine Tutorial]
* [http://www-immuno.path.cam.ac.uk/~immuno/part1/lec09/lec10_99.html Cell Interactions: Cytokines]. inactive link
*[https://web.archive.org/web/20110726174120/https://www.immport.org/immportWeb/queryref/geneListSummary.do Cytokine Gene Summary, Ontology, Pathways and More: Immunology Database and Analysis Portal (ImmPort)]
* [http://www.emedicine.com/neuro/topic602.htm Reperfusion Injury in Stroke].
*{{EMedicine|article|1162437|Reperfusion Injury in Stroke}}
* [http://www.copewithcytokines.de CopeWithCytoKines Cytokines Online Pathfinder Encyclopaedia]


{{Cell signaling}}
{{Cytokines}}
{{Intercellular signaling peptides and proteins}}
{{Immune system}}
{{Immune system}}
{{Intercellular signaling peptides and proteins}}
{{Cytokines}}

[[Category:Cytokines|Cytokines]]


*[[Interleukin-12]] (IL-12),secreted by Macrophage and act on THo (t-helper cell 0) and convert into TH1 (t-helper cell 1)which produce γ-IF.γ-IF activates Macrophage into super active cell which start cell mediated response.

== Cysteine-knot cytokines ==
{{Expand section|date=February 2007}}

Members of the [[transforming growth factor beta superfamily]] belong to this group, including [[TGF beta 1|TGF-β1]], [[TGF beta 2|TGF-β2]] and [[TGF beta 3|TGF-β3]].

== See also ==
* [[Active Hexose Correlated Compound]]
* [[Adipokine]]s
* [[Apoptosis]]
* [[Secretion assay|Cytokine secretion assay]]
* [[Chemokine]]
* [[Cytokine storm]]
* [[ELISA]] assays
* [[ELISPOT]] assays
* [[FluoroSpot]] assays
* [[Granulocyte-colony stimulating factor]]
* [[Interleukin-7]]
* [[Lymphokine]]
* [[Signal transduction]]
* [[TSLP]]

== Notes ==
{{Commons category|Cytokines}}
<references group="nb" />

== References ==
{{reflist|2}}

== External links ==
* [https://www.immport.org/immportWeb/queryref/geneListSummary.do Cytokine Gene Summary, Ontology, Pathways and More - Immunology Database and Analysis Portal (ImmPort)]
* [http://microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html Cytokine Tutorial]. dead link.
* [http://www-immuno.path.cam.ac.uk/~immuno/part1/lec09/lec10_99.html Cell Interactions: Cytokines]. inactive link
* [http://www.emedicine.com/neuro/topic602.htm Reperfusion Injury in Stroke].
* [http://www.copewithcytokines.de CopeWithCytoKines Cytokines Online Pathfinder Encyclopaedia]

{{Cell signaling}}
{{Cell signaling}}
{{Cytokine receptor modulators}}
{{Immune system}}
{{Authority control}}
{{Intercellular signaling peptides and proteins}}
{{Portal bar|Biology}}
{{Cytokines}}


[[Category:Cytokines|Cytokines]]
[[Category:Cytokines| ]]
[[Category:Immune system|*]]
[[Category:Immunology]]

Latest revision as of 11:35, 2 January 2025

Not to be confused with Cytokinin, a class of plant hormones promoting cell division.

3D medical animation still showing secretion of cytokines

Cytokines (/ˈsaɪtəkaɪn/)[1] are a broad and loose category of small proteins (~5–25 kDa[2]) important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology)[citation needed]. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.[3][4] They act through cell surface receptors and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. They are different from hormones, which are also important cell signaling molecules. Hormones circulate in higher concentrations, and tend to be made by specific kinds of cells. Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.

The word comes from the ancient Greek language: cyto, from Greek κύτος, kytos, 'cavity, cell' + kines, from Greek κίνησις, kinēsis, 'movement'.

Discovery

[edit]

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication.[5] The activity of interferon-gamma (the sole member of the interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator.[6] Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.[7][8]

In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines".[9] In 1974, pathologist Stanley Cohen, M.D. (not to be confused with the Nobel laureate named Stanley Cohen, who was a PhD biochemist; nor with the MD geneticist Stanley Norman Cohen) published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine.[10] In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.[11]

Difference from hormones

[edit]

Classic hormones circulate in aqueous solution in nanomolar (10-9 M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10-12 M) concentrations that can increase up to 1,000 times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α.[12] In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas.[13] The current terminology refers to cytokines as immunomodulating agents.

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic (i.e., affecting the whole organism) rather than local. For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

A scalable vector graphic of signal transduction pathways
Cytokines typically activate second messenger systems, like JAK-STAT pathways, as illustrated on the left side of the diagram. Conversely, hormones typically activate different signaling pathways, like G protein-coupled receptors, seen at the top of the figure.

Nomenclature

[edit]

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.

  • The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally white blood cells (leukocytes). It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
  • Lymphokines: produced by lymphocytes
  • Monokines: produced exclusively by monocytes
  • Interferons: involved in antiviral responses
  • Colony stimulating factors: support the growth of cells in semisolid media
  • Chemokines: mediate chemoattraction (chemotaxis) between cells.

Classification

[edit]

Structural

[edit]

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:

  1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO).[14] They can be grouped into long-chain and short-chain cytokines by topology.[15] Some members share the common gamma chain as part of their receptor.[16]
  2. the interferon (IFN) subfamily.
  3. the IL-10 subfamily.

Functional

[edit]

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and those that enhance antibody responses, type 2 (TGF-β, IL-4, IL-10, IL-13, etc.). A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders. Several inflammatory cytokines are induced by oxidative stress.[17][18] The fact that cytokines themselves trigger the release of other cytokines [19][20][21] and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.[22] There are both pro-inflammatory and anti-inflammatory cytokines that regulate this[clarification needed] pathway.

Receptors

[edit]
Main article: Cytokine receptor

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.

A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.

  • Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
  • Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
  • Interferon (type 2) family, whose members are receptors for IFN β and γ.
  • Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named.
  • Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.[citation needed]
  • Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.[23]

Cellular effects

[edit]

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of[24] T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[24] Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread papular eruptions.[25]

Roles in health and disease

[edit]

Cytokines are involved in several developmental processes during embryonic development.[26][nb 1][27][nb 2] Cytokines are released from the blastocyst, and are also expressed in the endometrium, and have critical roles in the stages of zona hatching, and implantation.[28] Cytokines are crucial for fighting off infections and in other immune responses.[29] However, they can become dysregulated and pathological in inflammation, trauma, sepsis,[29] and hemorrhagic stroke.[30] Dysregulated cytokine secretion in the aged population can lead to inflammaging, and render these individuals more vulnerable to age-related diseases like neurodegenerative diseases and type 2 diabetes.[31]

A 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.[32]

A 2024 study found a positive correlation between plasma interleukin IL-2 and fatigue in patients with type 1 narcolepsy.[33]

Adverse effects

[edit]

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression[34] and Alzheimer's disease[35] to cancer.[36] T regulatory cells (Tregs) and related-cytokines are effectively engaged in the process of tumor immune escape and functionally inhibit immune response against the tumor. Forkhead box protein 3 (Foxp3) as a transcription factor is an essential molecular marker of Treg cells. Foxp3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β.[37] Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity.[38]

Over-secretion of cytokines can trigger a dangerous cytokine storm syndrome. Cytokine storms may have been the cause of severe adverse events during a clinical trial of TGN1412. Cytokine storms are also suspected to have been the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels. Another example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade, resulting in the systemic inflammatory response syndrome and multi-organ failure associated with this intra-abdominal catastrophe.[39] In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms.[40][41][42] Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections.[43]

Medical use as drugs

[edit]

Some cytokines have been developed into protein therapeutics using recombinant DNA technology.[44] Recombinant cytokines being used as drugs as of 2014 include:[45]

See also

[edit]

Notes

[edit]
  1. ^ Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)
  2. ^ Chen explains the regulatory activity of LIF in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner." (719)

References

[edit]
  1. ^ "CYTOKINE". dictionary.cambridge.org. Retrieved 27 September 2024.
  2. ^ Janeway's Immunobiology. Garland Science. 2017. p. 107. ISBN 978-0-8153-4551-0.
  3. ^ Lackie J (2010). "Cytokines". A Dictionary of Biomedicine. Oxford University Press. ISBN 978-0-19-954935-1.
  4. ^ "Cytokine". Stedman's Medical Dictionary (28th ed.). Wolters Kluwer Health, Lippincott Williams & Wilkins. 2006. ISBN 978-0-7817-6450-6.
  5. ^ Isaacs A, Lindenmann J (September 1957). "Virus interference. I. The interferon". Proc. R. Soc. Lond. B Biol. Sci. 147 (927): 258–267. Bibcode:1957RSPSB.147..258I. doi:10.1098/rspb.1957.0048. PMID 13465720. S2CID 202574492.
  6. ^ Wheelock EF (July 1965). "Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin". Science. 149 (3681): 310–311. Bibcode:1965Sci...149..310W. doi:10.1126/science.149.3681.310. PMID 17838106. S2CID 1366348.
  7. ^ Bloom BR, Bennett B (July 1966). "Mechanism of a reaction in vitro associated with delayed-type hypersensitivity". Science. 153 (3731): 80–82. Bibcode:1966Sci...153...80B. doi:10.1126/science.153.3731.80. PMID 5938421. S2CID 43168526.
  8. ^ David JR (July 1966). "Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction". Proc. Natl. Acad. Sci. U.S.A. 56 (1): 72–77. Bibcode:1966PNAS...56...72D. doi:10.1073/pnas.56.1.72. PMC 285677. PMID 5229858.
  9. ^ Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT (October 1969). ""Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation". Nature. 224 (5214): 38–42. Bibcode:1969Natur.224...38D. doi:10.1038/224038a0. PMID 5822903. S2CID 4172811.
  10. ^ Cohen S, Bigazzi PE, Yoshida T (April 1974). "Commentary. Similarities of T cell function in cell-mediated immunity and antibody production". Cell. Immunol. 12 (1): 150–159. doi:10.1016/0008-8749(74)90066-5. PMID 4156495.
  11. ^ Ogawa M (1993). "Differentiation and proliferation of hematopoetic stem cells". Blood. 81 (11): 2844–2853. doi:10.1182/blood.V81.11.2844.2844. PMID 8499622.
  12. ^ Boyle JJ (January 2005). "Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture". Current Vascular Pharmacology. 3 (1): 63–68. CiteSeerX 10.1.1.324.9948. doi:10.2174/1570161052773861. PMID 15638783.
  13. ^ Cannon JG (December 2000). "Inflammatory Cytokines in Nonpathological States". News in Physiological Sciences. 15 (6): 298–303. doi:10.1152/physiologyonline.2000.15.6.298. PMID 11390930.
  14. ^ Leonard WJ (December 2001). "Cytokines and immunodeficiency diseases". Nature Reviews. Immunology. 1 (3): 200–208. doi:10.1038/35105066. PMID 11905829. S2CID 5466985.
  15. ^ Rozwarski DA, Gronenborn AM, Clore GM, Bazan JF, Bohm A, Wlodawer A, et al. (March 1994). "Structural comparisons among the short-chain helical cytokines". Structure. 2 (3): 159–173. doi:10.1016/s0969-2126(00)00018-6. PMID 8069631.
  16. ^ Reche PA (April 2019). "The tertiary structure of γc cytokines dictates receptor sharing". Cytokine. 116: 161–168. doi:10.1016/j.cyto.2019.01.007. PMID 30716660. S2CID 73449371.
  17. ^ Vlahopoulos S, Boldogh I, Casola A, Brasier AR (September 1999). "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation". Blood. 94 (6): 1878–1879. doi:10.1182/blood.V94.6.1878.418k03_1878_1889. PMID 10477716. S2CID 25974629.
  18. ^ David F, Farley J, Huang H, Lavoie JP, Laverty S (April 2007). "Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes". Vet Surg. 36 (3): 221–227. doi:10.1111/j.1532-950X.2007.00253.x. PMID 17461946.
  19. ^ Chokkalingam V, Tel J, Wimmers F, Liu X, Semenov S, Thiele J, et al. (December 2013). "Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics". Lab Chip. 13 (24): 4740–4744. doi:10.1039/c3lc50945a. PMID 24185478. Archived from the original on 29 November 2020. Retrieved 21 November 2020.
  20. ^ Carpenter LR, Moy JN, Roebuck KA (March 2002). "Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1". BMC Infect. Dis. 2: 5. doi:10.1186/1471-2334-2-5. PMC 102322. PMID 11922866.
  21. ^ Tian B, Nowak DE, Brasier AR (September 2005). "A TNF-induced gene expression program under oscillatory NF-kappaB control". BMC Genomics. 6: 137. doi:10.1186/1471-2164-6-137. PMC 1262712. PMID 16191192.
  22. ^ Zhang JM, An J (2007). "Cytokines, inflammation, and pain". Int Anesthesiol Clin. 45 (2): 27–37. doi:10.1097/AIA.0b013e318034194e. PMC 2785020. PMID 17426506.
  23. ^ Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nat. Rev. Immunol. 9 (8): 556–567. doi:10.1038/nri2586. PMC 2821718. PMID 19575028.
  24. ^ a b Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. (April 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine. 16 (4): 452–459. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540.
  25. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.[page needed]
  26. ^ Saito S (2001). "Cytokine cross-talk between mother and the embryo/placenta". J. Reprod. Immunol. 52 (1–2): 15–33. doi:10.1016/S0165-0378(01)00112-7. PMID 11600175.
  27. ^ Chen HF, Shew JY, Ho HN, Hsu WL, Yang YS (October 1999). "Expression of leukemia inhibitory factor and its receptor in preimplantation embryos". Fertil. Steril. 72 (4): 713–719. doi:10.1016/S0015-0282(99)00306-4. PMID 10521116.
  28. ^ Seshagiri PB, Vani V, Madhulika P (March 2016). "Cytokines and Blastocyst Hatching". American Journal of Reproductive Immunology. 75 (3): 208–217. doi:10.1111/aji.12464. PMID 26706391. S2CID 11540123.
  29. ^ a b Dinarello CA (August 2000). "Proinflammatory cytokines". Chest. 118 (2): 503–508. doi:10.1378/chest.118.2.503. PMID 10936147.
  30. ^ Zhu H, Wang Z, Yu J, et al. (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610. doi:10.1016/j.pneurobio.2019.03.003. PMID 30923023. S2CID 85495400.
  31. ^ Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. (June 2000). "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences. 908 (1): 244–254. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. ISSN 0077-8923. PMID 10911963. S2CID 1843716.
  32. ^ Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S (24 August 2019). "A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)". BMC Neurology. 19 (1): 207. doi:10.1186/s12883-019-1433-0. PMC 6708220. PMID 31445522.
  33. ^ Yang Q, Wu Q, Zhan Q, Deng L, Ding Y, Wang F, et al. (February 2024). "Association between cytokines and fatigue in patients with type 1 narcolepsy". Journal of Clinical Neuroscience. 120 (1): 102. doi:10.1016/j.jocn.2024.01.007.
  34. ^ Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. (March 2010). "A meta-analysis of cytokines in major depression". Biol. Psychiatry. 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID 20015486. S2CID 230209.
  35. ^ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease". Biol. Psychiatry. 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646. S2CID 6544784.
  36. ^ Locksley RM, Killeen N, Lenardo MJ (February 2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell. 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407. S2CID 7657797.
  37. ^ Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, et al. (February 2021). "Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients". Cytokine. 138: 155351. doi:10.1016/j.cyto.2020.155351. ISSN 1043-4666. PMID 33127257. S2CID 226218796.
  38. ^ Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, et al. (August 2015). "Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment". Cytokine Growth Factor Rev. 26 (4): 389–403. doi:10.1016/j.cytogfr.2015.06.001. PMC 4526340. PMID 26119834.
  39. ^ Makhija R, Kingsnorth AN (2002). "Cytokine storm in acute pancreatitis". Journal of Hepato-Biliary-Pancreatic Surgery. 9 (4): 401–410. doi:10.1007/s005340200049. PMID 12483260.
  40. ^ Cron R, Chatham WW (12 March 2020). "How doctors can potentially significantly reduce the number of deaths from Covid-19". Vox. Retrieved 14 March 2020.
  41. ^ Ruan Q, Yang K, Wang W, Jiang L, Song J (May 2020). "Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China". Intensive Care Medicine. 46 (5): 846–848. doi:10.1007/s00134-020-05991-x. PMC 7080116. PMID 32125452.
  42. ^ Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (March 2020). "COVID-19: consider cytokine storm syndromes and immunosuppression". Lancet. 395 (10229): 1033–1034. doi:10.1016/S0140-6736(20)30628-0. PMC 7270045. PMID 32192578.
  43. ^ Cascella M, Rajnik M, Cuomo A, et al. (4 October 2020). Features, Evaluation, and Treatment of Coronavirus. StatPearls Publishing. PMID 32150360. Retrieved 4 December 2020.
  44. ^ De Root AS, Scott DW (November 2007). "Immunogenicity of protein therapeutics". Trends in Immunology. 28 (11): 482–490. doi:10.1016/j.it.2007.07.011. PMID 17964218.
  45. ^ Dimitrov DS (2012). "Therapeutic Proteins". Methods in Molecular Biology. Vol. 899. pp. 1–26. doi:10.1007/978-1-61779-921-1_1. ISBN 978-1-61779-920-4. PMC 6988726. PMID 22735943.
  46. ^ Woodman RC, Erickson RW, Rae J, Jaffe HS, Curnutte JT (March 1992). "Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity". Blood. 79 (6): 1558–1562. doi:10.1182/blood.v79.6.1558.bloodjournal7961558. PMID 1312372.
  47. ^ Key LL, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, et al. (June 1995). "Long-term treatment of osteopetrosis with recombinant human interferon gamma". N. Engl. J. Med. 332 (24): 1594–1599. doi:10.1056/NEJM199506153322402. PMID 7753137.
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