User:Caffepenia/沙盒3
細胞激素 (英文：Cytokine)是一類為了細胞傳訊的小分子蛋白(分子量約5~20kDa)，能作用在周圍的細胞。細胞激素透過自分泌、旁分泌與內分泌參予免疫調控，但它們與荷爾蒙的分野尚在研究中。細胞激素中包含了化學驅動激素、干擾素、介白素、淋巴激素和腫瘤壞死因子但多不含荷爾蒙與生长因子。細胞激素可由多種細胞分泌，像是免疫細胞(如：巨噬细胞、B细胞、T细胞與肥大细胞)，或由內皮細胞、纖維母細胞與多種基质细胞分泌，同一細胞激素可由多種細胞分泌。[1][2][3]
他們透過目標細胞受體作用，這點對免疫系統尤其重要。細胞激素調控體液免疫與細胞介導免疫之間的平衡，也控管特定細胞的發育、成熟、生長和反應。某些細胞激素間會彼此促進或抑制分泌。[3]
雖然和荷爾蒙類似，都是細胞傳訊的重要分子，但兩者仍有不同：荷爾蒙在體內循環的量較恆定，而且多由特定細胞分泌。
細胞激素對健康和疾病很重要，尤其是在人體應對感染、免疫反應、發炎、創傷、敗血症、癌症與生殖時。
此外，細胞激素之英文 "cytokine" 之cyto來自希腊语 "κύτος" , kytos，「細胞或空腔」之意加上kines來自希臘語"κίνησις", kinēsis，「移動」之意。
細胞激素的發現
[编辑]干擾素α，一種第一型干擾素，於1957年時被發現是會影響病毒複製的蛋白質。[4]干擾素γ(the sole member of the 第二型干擾素的主要成員)的作用則在1965年被發現，是第一個被辨認的淋巴球分泌的調節物。[5]巨噬細胞遷移抑制因子(MIF)同時由John David和Barry Bloom於1966年發現。[6][7]
1969年時，Dudley Dumonde提出了｢淋巴激素｣("lymphokine")的術語來描述淋巴球分泌的蛋白質。後續由巨噬細胞及單核球分泌的則稱｢單核球激素｣("monokine")。[8]
1974年，Stanley Cohen發表了一篇描述受病毒感染的纖維母細胞製造MIF的專欄文章，顯示細胞激素的製造不只侷限在免疫細胞。這促使他提出｢細胞激素｣這個術語。[9]
與荷爾蒙的差別
[编辑]一般來說，體內循環荷爾蒙的量約是奈莫耳濃度(10-9 M)，而且改變量通常在一個數量級內；相比之下，細胞激素(如介白素6)是以皮莫耳濃度(10-12 M) 在體內循環，但是當遇到創傷或感染時能增加到1000倍。此外，分泌細胞激素的細胞是很廣泛多樣的，這也是兩者之間的不同。差不多所有的有何細胞，尤其是內皮細胞、表皮細胞和常駐的巨噬細胞(多鄰近與外部環境之間的交界)都能製造IL-1、IL-6和TNF-α。[10]相形之下，典型的荷爾蒙(如：胰島素)是被特定分泌腺(如：胰臟)分泌的。[11]自2008年起便有了細胞激素這個現代命名來指稱這些免疫調節因子。然而兩者之間的界線仍有點模糊，因為有些細胞激素的免疫調控效果是全身性而非區域性的，所以需要更多研究來分別。
A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic 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.
命名
[编辑]細胞激素因為其功能、分泌細胞或作用目標不同，被分類為淋巴因子、介白素和化學趨化因子。因為細胞激素的特色是有很多冗餘性或基因多效性，所以底下的分類常會有例外及過時。
- 介白素：介白素最早是由研究者用於目標細胞主要是白血球]的細胞激素。現在則主要用在命名新發現的細胞激素，與其主要功能較無關係。他們絕大多數由輔助型T細胞分泌。
- 淋巴因子：由淋巴球分泌。
- 單核球因子：由單核球分泌。
- 干擾素：參與對付病毒。
- 株落刺激因子：能支持在半固態培養基中細胞的生長。
- 化學趨化因子：調控細胞間的化學趨化性。
分類
[编辑]結構性分類
[编辑]按結構的同源性可以分成四類，這四類之間的結構冗餘性也較少：
- 有四個α螺旋束的家族：他們的蛋白質三維結構有四個α螺旋束，而其中又分為三個亞家族。
- IL-1 家族：主要有IL-1和IL-18。
- IL-17 家族
- 半胱胺酸類家族：其中包含轉換生長因子-β蛋白質超家族，如：轉換生長因子-β1、轉換生長因子-β2、轉換生長因子-β3。
Functional
[编辑]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 type 2 (TGF-β, IL-4, IL-10, IL-13, etc.), which favor antibody responses.
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.[12][13] The fact that cytokines themselves trigger the release of other cytokines[14][15][16] 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.[17] There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway.
Receptors
[编辑]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 (TNF).
- 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.[來源請求]
- 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.[18]
Cellular effects
[编辑]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.
Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of[19] 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.[19]
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.[20]
Roles of endogenous cytokines in health and disease
[编辑]Cytokines are often involved in several developmental processes during embryogenesis.[21][nb 1][22][nb 2]
Cytokines are crucial for fighting off infections and in other immune responses.[23] However, they can become dysregulated and pathological in inflammation, trauma, and sepsis.[23]
Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression[24] and Alzheimer's disease[25] to cancer.[26] 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.[27] 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 are suspected to be the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, due to its ability to produce stronger immune responses, likely increasing cytokine levels. Another important 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.[28]
Medical use as drugs
[编辑]Some cytokines have been developed into protein therapeutics using recombinant DNA technology.[29] Recombinant cytokines being used as drugs as of 2014 include:[30]
- Bone morphogenetic protein (BMP), used to treat bone-related conditions
- Erythropoietin (EPO), used to treat anemia
- Granulocyte colony-stimulating factor (G-CSF), used to treat neutropenia in cancer patients
- Granulocyte macrophage colony-stimulating factor (GM-CSF), used to treat neutropenia and fungal infections in cancer patients
- Interferon alfa, used to treat hepatitis C and multiple sclerosis
- Interferon beta, used to treat multiple sclerosis
- Interleukin 2 (IL-2), used to treat cancer.
- Interleukin 11 (IL-11), used to treat thrombocytopenia in cancer patients.
- Interferon gamma is used to treat chronic granulomatous disease[31] and osteopetrosis[32]
Research into diagnostic use of measured levels
[编辑]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,[33] as well as immunomodulatory effects of foods or drugs.[34] In addition, elevated levels of IL-7, an important cytokine involved in T cell homeostasis, have been detected in the plasma of HIV-infected patients.[35]
See also
[编辑]Notes
[编辑]- ^ 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)
- ^ 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
[编辑]- ^ "Cytokine" in John Lackie. A Dictionary of Biomedicine. Oxford University Press. 2010. ISBN 9780199549351
- ^ "Cytokine" in Stedman’s Medical Dictionary, 28th ed. Wolters Kluwer Health, Lippincott, Williams & Wilkins (2006)
- ^ 3.0 3.1 Horst Ibelgaufts. Cytokines in Cytokines & Cells Online Pathfinder Encyclopedia Version 31.4 (Spring/Summer 2013 Edition)
- ^ ISAACS A, LINDENMANN J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957 Sep 12;147(927):258-67. PubMed PMID 13465720.
- ^ Wheelock EF. Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin. Science. 1965 Jul 16;149(3681):310-1. PubMed PMID 17838106.
- ^ Bloom B.R., Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 1966;153:80–82.
- ^ David J.R. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci USA. 1966;56:72–77.
- ^ Dumonde, D.C., Wolstencroft, R.A., Panayi, G.S., Matthew, M., Morley, J., and Howson, W.T. (1969). “Lymphokines”: Non-Antibody Mediators of Cellular Immunity generated by Lymphocyte Activation. Nature 224, 38.
- ^ Cohen, S., Bigazzi, P. E., Yoshida, T. (1974) Commentary. Similarities of T cell function in cell‐mediated immunity and antibody production. Cell. Immunol. 12, 150–159.
- ^ Boyle JJ. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol. January 2005, 3 (1): 63–8. PMID 15638783. doi:10.2174/1570161052773861.
- ^ Cannon JG. Inflammatory Cytokines in Nonpathological States. News Physiol. Sci. December 2000, 15: 298–303. PMID 11390930.
- ^ Vlahopoulos S, Boldogh I, Casola A, Brasier AR; Boldogh; Casola; Brasier. 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. September 1999, 94 (6): 1878–89. PMID 10477716.
- ^ David F, Farley J, Huang H, Lavoie JP, Laverty S; Farley; Huang; Lavoie; Laverty. Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes. Vet Surg. April 2007, 36 (3): 221–7. PMID 17461946. doi:10.1111/j.1532-950X.2007.00253.x.
- ^ Chokkalingam, V.; Tel, J.; Wimmers, F.; Liu, X.; Semenov, S.; Thiele, J.; Figdor, C. G.; Huck, W. T. S. Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics. Lab on a Chip. 2013, 13 (24): 4740–4744. PMID 24185478. doi:10.1039/C3LC50945A.
- ^ Carpenter LR, Moy JN, Roebuck KA; Moy; Roebuck. Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1. BMC Infect. Dis. March 2002, 2: 5. PMC 102322
. PMID 11922866. doi:10.1186/1471-2334-2-5.
- ^ Tian B, Nowak DE, Brasier AR; Nowak; Brasier. A TNF-induced gene expression program under oscillatory NF-kappaB control. BMC Genomics. 2005, 6: 137. PMC 1262712 . PMID 16191192. doi:10.1186/1471-2164-6-137.
- ^ Zhang, Jun-Ming; An, Jianxiong. Cytokines, Inflammation and Pain. International anesthesiology clinics. 2007-01-01, 45 (2): 27–37. ISSN 0020-5907. PMC 2785020 . PMID 17426506. doi:10.1097/AIA.0b013e318034194e.
- ^ Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. August 2009, 9 (8): 556–67. PMC 2821718 . PMID 19575028. doi:10.1038/nri2586.
- ^ 19.0 19.1 Said EA, Dupuy FP, Trautmann L, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. April 2010, 16 (4): 452–9. PMC 4229134 . PMID 20208540. doi:10.1038/nm.2106.
- ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.[页码请求]
- ^ Saito S. Cytokine cross-talk between mother and the embryo/placenta. J. Reprod. Immunol. 2001, 52 (1–2): 15–33. PMID 11600175. doi:10.1016/S0165-0378(01)00112-7.
- ^ Chen HF, Shew JY, Ho HN, Hsu WL, Yang YS; Shew; Ho; Hsu; Yang. Expression of leukemia inhibitory factor and its receptor in preimplantation embryos. Fertil. Steril. October 1999, 72 (4): 713–9. PMID 10521116. doi:10.1016/S0015-0282(99)00306-4.
- ^ 23.0 23.1 Dinarello CA. Proinflammatory cytokines. Chest. August 2000, 118 (2): 503–8. PMID 10936147. doi:10.1378/chest.118.2.503.
- ^ Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry. March 2010, 67 (5): 446–57. PMID 20015486. doi:10.1016/j.biopsych.2009.09.033.
- ^ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N; Lanctôt; Rothenburg; Wong; Cappell; Herrmann. A meta-analysis of cytokines in Alzheimer's disease. Biol. Psychiatry. November 2010, 68 (10): 930–41. PMID 20692646. doi:10.1016/j.biopsych.2010.06.012.
- ^ Locksley RM, Killeen N, Lenardo MJ; Killeen; Lenardo. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. February 2001, 104 (4): 487–501. PMID 11239407. doi:10.1016/S0092-8674(01)00237-9.
- ^ Vlahopoulos, SA; Cen, O; Hengen, N; Agan, J; Moschovi, M; Critselis, E; Adamaki, M; Bacopoulou, F; Copland, JA; Boldogh, I; Karin, M; Chrousos, GP. Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment.. Cytokine & Growth Factor Reviews. 20 June 2015, 26: 389–403. PMC 4526340 . PMID 26119834. doi:10.1016/j.cytogfr.2015.06.001.
- ^ Makhija R, Kingsnorth AN; Kingsnorth. Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002, 9 (4): 401–10. PMID 12483260. doi:10.1007/s005340200049.
- ^ Horst Ibelgaufts. Recombinant cytokines in Cytokines & Cells Online Pathfinder Encyclopedia Version 31.4 (Spring/Summer 2013 Edition)
- ^ Dimiter S. Dimitrov. Therapeutic Proteins.Chapter 1 in Therapeutic Proteins: Methods and Protocols, Editors: Vladimir Voynov, Justin A. Caravella. Volume 899 of Methods in Molecular Biology. Springer Science+Business Media, LLC 2012. ISBN 978-1-61779-920-4 (Print) 978-1-61779-921-1 (Online)
- ^ Woodman, RC; Erickson, RW; Rae, J; Jaffe, HS; Curnutte, JT. Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity.. Blood. Mar 15, 1992, 79 (6): 1558–62. PMID 1312372.
- ^ Key LL, Jr; Rodriguiz, RM; Willi, SM; Wright, NM; Hatcher, HC; Eyre, DR; Cure, JK; Griffin, PP; Ries, WL. Long-term treatment of osteopetrosis with recombinant human interferon gamma. The New England Journal of Medicine. Jun 15, 1995, 332 (24): 1594–9. PMID 7753137. doi:10.1056/NEJM199506153322402.
- ^ Kokkonen, H. Arthritis & Rheumatism, Feb. 2, 2010; vol 62: pp 383–391
- ^ Nikolaeva LG, Maystat TV, Masyuk LA, Pylypchuk VS, Volyanskii YL, Kutsyna GA; Maystat; Masyuk; Pylypchuk; Volyanskii; Kutsyna. Changes in CD4+ T-cells and HIV RNA resulting from combination of anti-TB therapy with Dzherelo in TB/HIV dually infected patients. Drug Des Devel Ther. 2009, 2: 87–93. PMC 2761183 . PMID 19920896.
- ^ Napolitano LA, Grant RM, Deeks SG, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat. Med. January 2001, 7 (1): 73–9. PMID 11135619. doi:10.1038/83381.
External links
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