Array ( [0] => {{Short description|Broad and loose category of small proteins important in cell signaling}} [1] => {{cs1 config|name-list-style=vanc|display-authors=6}} [2] => {{Distinguish|text=[[Cytokinin]], a class of plant hormones promoting cell division}} [3] => {{Use dmy dates|date=November 2017}} [4] => [[File:Cytokine release.jpg|thumb|264x264px|3D [[medical animation]] still showing secretion of cytokines]] [5] => '''Cytokines''' are a broad and loose category of small [[protein]]s (~5–25 [[kDa]]{{cite book|title=Janeway's Immunobiology|publisher=Garland Science|year=2017|isbn=978-0-8153-4551-0|pages=107|language=english}}) 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]]. [6] => [7] => 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]]). 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.{{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 }}{{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 }} 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. [8] => [9] => The word comes from the ancient [[Greek language]]: ''cyto'', from Greek κύτος, ''kytos'', 'cavity, cell' + ''kines'', from Greek κίνησις, ''kinēsis'', 'movement'. [10] => [11] => == Discovery == [12] => [13] => Interferon-alpha, an [[interferon type I]], was identified in 1957 as a protein that interfered with viral replication.{{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 }} 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.{{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 }} [[Macrophage migration inhibitory factor]] (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.{{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 }}{{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 }} [14] => [15] => 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".{{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 }} In 1974, pathologist [[Stanley Cohen (biochemist)|Stanley Cohen]], M.D. (not to be confused with the [[Stanley Cohen (biochemist)|Nobel laureate]]) 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.{{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 }} Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.{{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}} [16] => [17] => ==Difference from hormones== [18] => 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]].{{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 }} In contrast, classic hormones, such as [[insulin]], are secreted from discrete [[gland]]s such as the [[pancreas]].{{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 }} The current terminology refers to cytokines as [[Immunotherapy|immunomodulating agents]]. [19] => [20] => 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. [21] => [[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.]] [22] => [23] => == Nomenclature == [24] => 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. [25] => [26] => * 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. [27] => * ''Lymphokines'': produced by lymphocytes [28] => * ''Monokines'': produced exclusively by [[monocytes]] [29] => * ''Interferons'': involved in antiviral responses [30] => * ''[[Colony stimulating factors]]'': support the growth of cells in semisolid media [31] => * ''Chemokines'': mediate chemoattraction ([[chemotaxis]]) between cells. [32] => [33] => == Classification == [34] => [35] => === Structural === [36] => 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: [37] => [38] => *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: [39] => # the [[interleukin 2|IL-2]] subfamily. This is the largest family. It contains several non-immunological cytokines including [[erythropoietin]] (EPO) and [[thrombopoietin]] (TPO).{{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 }} They can be grouped into ''long-chain'' and ''short-chain'' cytokines by topology.{{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 }} Some members share the [[common gamma chain]] as part of their receptor.{{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 }} [40] => # the [[interferon|interferon (IFN)]] subfamily. [41] => # the [[interleukin 10|IL-10]] subfamily. [42] => *The [[interleukin 1|IL-1]] family, which primarily includes IL-1 and [[interleukin|IL-18]]. [43] => * 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]]. [44] => * 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. [45] => [46] => === Functional === [47] => 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]].{{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 }}{{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 }} The fact that cytokines themselves trigger the release of other cytokines {{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 }}{{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 }}{{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 }} 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.{{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 }} There are both pro-inflammatory and [[anti-inflammatory]] cytokines that regulate this pathway. [48] => [49] => == Receptors == [50] => {{Main|Cytokine receptor}} [51] => 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. [52] => [53] => 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. [54] => [55] => * [[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. [56] => * [[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]]). [57] => * Interferon (type 2) family, whose members are receptors for IFN β and γ. [58] => * [[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. [59] => * [[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}} [60] => * [[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.{{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 }} [61] => [62] => == Cellular effects == [63] => 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. [64] => [65] => It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of{{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 }} 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. 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]].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}} [66] => [67] => ==Roles in health and disease== [68] => Cytokines are involved in several developmental processes during [[embryonic development]].{{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}}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){{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 }}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) 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]].{{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 }} Cytokines are crucial for fighting off infections and in other immune responses.{{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 }} However, they can become dysregulated and pathological in [[inflammation]], trauma, [[sepsis]], and [[hemorrhagic stroke]].{{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 }} 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.{{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}} [69] => [70] => A 2019 review was inconclusive as to whether cytokines play any definitive role in [[ME/CFS]].{{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}} [71] => [72] => ==Adverse effects== [73] => [74] => Adverse effects of cytokines have been linked to many disease states and conditions ranging from [[schizophrenia]], [[major depression]]{{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 }} and [[Alzheimer's disease]]{{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 }} to [[cancer]].{{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 }} 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]].{{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 }} [75] => 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.{{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 }} [76] => [77] => 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 be 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.{{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}} In the [[COVID-19 pandemic]], some deaths from [[Coronavirus disease 2019|COVID-19]] have been attributable to cytokine release storms.{{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}}{{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}}{{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}} Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in [[Coronavirus disease 2019|COVID-19]] infections.{{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}} [78] => [79] => ==Medical use as drugs== [80] => [81] => Some cytokines have been developed into [[Biologic medical product|protein therapeutics]] using [[recombinant DNA]] technology.{{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}} Recombinant cytokines being used as drugs as of 2014 include:{{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}} [82] => * [[Bone morphogenetic protein]] (BMP), used to treat bone-related conditions [83] => * [[Erythropoietin]] (EPO), used to treat [[anemia]] [84] => * [[Granulocyte colony-stimulating factor]] (G-CSF), used to treat [[neutropenia]] in cancer patients [85] => * [[Granulocyte macrophage colony-stimulating factor]] (GM-CSF), used to treat [[neutropenia]] and [[fungal infections]] in cancer patients [86] => * [[Interferon alfa]], used to treat [[hepatitis C]] and [[multiple sclerosis]] [87] => * [[Interferon beta]], used to treat [[multiple sclerosis]] [88] => * [[Interleukin 2]] (IL-2), used to treat cancer. [89] => * [[Interleukin 11]] (IL-11), used to treat [[thrombocytopenia]] in cancer patients. [90] => * [[Interferon gamma]] is used to treat [[chronic granulomatous disease]]{{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 }} and [[osteopetrosis]]{{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 }} [91] => [92] => == See also == [93] => {{Div col}} [94] => *[[Adipokine]]s [95] => *[[Apoptosis]] [96] => *[[Cytokine redundancy]] [97] => *[[Cytokine release syndrome]] [98] => *[[Secretion assay|Cytokine secretion assay]] [99] => *[[ELISA]] assays [100] => *[[Myokine]] [101] => *[[Signal transduction]] [102] => *[[Thymic stromal lymphopoietin]] [103] => *[[Virokine]] [104] => {{Div col end}} [105] => [106] => == Notes == [107] => [108] => [109] => == References == [110] => {{reflist|30em}} [111] => [112] => ==External links== [113] => {{Commons category|Cytokines}} [114] => *[http://www.cytokinesignalling.com Cytokine Signalling Forum] [115] => *[http://www.elisakits.co.uk/immunology-cytokines/cytokine-tutorial Cytokine Tutorial] [116] => *[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)] [117] => *{{EMedicine|article|1162437|Reperfusion Injury in Stroke}} [118] => [119] => {{Cytokines}} [120] => {{Intercellular signaling peptides and proteins}} [121] => {{Immune system}} [122] => {{Cell signaling}} [123] => {{Cytokine receptor modulators}} [124] => {{Authority control}} [125] => {{Portal bar|Biology}} [126] => [127] => [[Category:Cytokines| ]] [128] => [[Category:Immune system|*]] [129] => [[Category:Immunology]] [] => )
good wiki

Cytokine

Cytokines are small proteins that play a crucial role in cell signaling and immune responses in the human body. They are produced by various cells, including white blood cells, and act as messengers between cells, regulating cell growth, inflammation, and immune function.

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They are produced by various cells, including white blood cells, and act as messengers between cells, regulating cell growth, inflammation, and immune function. Cytokines can have both pro-inflammatory and anti-inflammatory effects, and their dysregulation has been linked to various diseases, including cancer, autoimmune disorders, and infectious diseases. The Wikipedia page on cytokines provides comprehensive information on their functions, classification, signaling pathways, and clinical significance. It also covers the history of cytokine research, techniques used to study cytokines, and therapeutic approaches targeting cytokines for disease treatment. The page is well-referenced and serves as a valuable resource for researchers, students, and anyone interested in understanding the role of cytokines in human health and disease.

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