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细胞激素 (英文：Cytokine)是一类为了细胞传讯的小分子蛋白(分子量约5~20kDa)，能作用在周围的细胞。细胞激素透过自分泌、旁分泌与内分泌参予免疫调控，但它们与荷尔蒙的分野尚在研究中。细胞激素中包含了化学驱动激素、干扰素、介白素、淋巴激素和肿瘤坏死因子但多不含荷尔蒙与生长因子。细胞激素可由多种细胞分泌，像是免疫细胞(如：巨噬细胞、B细胞、T细胞与肥大细胞)，或由内皮细胞、纤维母细胞与多种基质细胞分泌，同一细胞激素可由多种细胞分泌。[1][2][3]
他们透过目标细胞受体作用，这点对免疫系统尤其重要。细胞激素调控体液免疫与细胞介导免疫之间的平衡，也控管特定细胞的发育、成熟、生长和反应。某些细胞激素间会彼此促进或抑制分泌。[3]
虽然和荷尔蒙类似，都是细胞传讯的重要分子，但两者仍有不同：荷尔蒙在体内循环的量较恒定，而且多由特定细胞分泌。
细胞激素对健康和疾病很重要，尤其是在人体应对感染、免疫反应、发炎、创伤、败血症、癌症与生殖时。
此外，细胞激素之英文 "cytokine" 之cyto来自希腊语 "κύτος" , kytos，“细胞或空腔”之意加上kines来自希腊语"κίνησις", kinēsis，“移动”之意。
细胞激素的发现
[编辑]干扰素α，一种第一型干扰素，于1957年时被发现是会影响病毒复制的蛋白质。[4]干扰素γ(the sole member of the 第二型干扰素的主要成员)的作用则在1965年被发现，是第一个被辨认的淋巴球分泌的调节物。[5]巨噬细胞迁移抑制因子(MIF)同时由John David和Barry Bloom于1966年发现。[6][7]
1969年时，Dudley Dumonde提出了“淋巴激素”("lymphokine")的术语来描述淋巴球分泌的蛋白质。后续由巨噬细胞及单核球分泌的则称“单核球激素”("monokine")。[8]
1974年，Stanley Cohen发表了一篇描述受病毒感染的纤维母细胞制造MIF的专栏文章，显示细胞激素的制造不只局限在免疫细胞。这促使他提出“细胞激素”这个术语。[9]
与荷尔蒙的差别
[编辑]一般来说，体内循环荷尔蒙的量约是奈莫耳浓度(10-9 M)，而且改变量通常在一个数量级内；相比之下，细胞激素(如介白素6)是以皮莫耳浓度(10-12 M) 在体内循环，但是当遇到创伤或感染时能增加到1000倍。此外，分泌细胞激素的细胞是很广泛多样的，这也是两者之间的不同。差不多所有的有何细胞，尤其是内皮细胞、表皮细胞和常驻的巨噬细胞(多邻近与外部环境之间的交界)都能制造IL-1、IL-6和TNF-α。[10]相形之下，典型的荷尔蒙(如：胰岛素)是被特定分泌腺(如：胰脏)分泌的。[11]自2008年起便有了细胞激素这个现代命名来指称这些免疫调节因子。然而两者之间的界线仍有点模糊，因为有些细胞激素的免疫调控效果是全身性而非区域性的，所以需要更多研究来分别。
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]细胞激素因为其功能、分泌细胞或作用目标不同，被分类为淋巴因子、介白素和化学趋化因子。因为细胞激素的特色是有很多冗余性或基因多效性，所以底下的分类常会有例外及过时。
- 介白素：介白素最早是由研究者用于目标细胞主要是白血球]的细胞激素。现在则主要用在命名新发现的细胞激素，与其主要功能较无关系。他们绝大多数由辅助型T细胞分泌。
- 淋巴因子：由淋巴球分泌。
- 单核球因子：由单核球分泌。
- 干扰素：参与对付病毒。
- 株落刺激因子：能支持在半固态培养基中细胞的生长。
- 化学趋化因子：调控细胞间的化学趋化性。
分类
[编辑]结构性分类
[编辑]按结构的同源性可以分成四类，这四类之间的结构冗余性也较少：
- 有四个α螺旋束的家族：他们的蛋白质三维结构有四个α螺旋束，而其中又分为三个亚家族。
- IL-1 家族：主要有IL-1和IL-18。
- IL-17 家族
- 半胱胺酸类家族：其中包含转换生长因子-β蛋白质超家族，如：转换生长因子-β1、转换生长因子-β2、转换生长因子-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.[来源请求]
- 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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