Cytokine

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 }}

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, 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.{{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 }} In 1993, 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}}

Classic hormones circulate in aqueous solution in nanomolar (10{{sup|-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{{sup|-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.{{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 glands 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 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.

File:Signal transduction pathways.svgs, 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.]]

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.

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-α-helix bundle family ({{InterPro|IPR009079}}): member cytokines have three-dimensional structures with a bundle of four α-helices. This family, in turn, is divided into three sub-families:

1. the 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 }}
2. the interferon (IFN) subfamily.
3. the IL-10 subfamily.

• The IL-1 family, which primarily includes IL-1 and IL-18.
• The cysteine knot cytokines ({{UniProt|IPR029034}}) include members of the transforming growth factor beta superfamily, including TGF-β1, TGF-β2 and TGF-β3.
• The 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.

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.{{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 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{{Clarify|reason=Which pathway?|date=July 2024}} pathway.

{{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 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|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.{{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 }}

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{{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 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 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}}

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 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.{{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}}

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}}

A 2024 study found a positive correlation between plasma interleukin IL-2 and fatigue in patients with type 1 narcolepsy.{{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= }}

Autoantibodies against cytokines also plays a role in health and disease. In 2020 neutralizing autoantibodies against type I interferons were reported in 10.2% of patients with life-threatening COVID-19.{{Cite journal |last=Bastard |first=Paul |last2=Rosen |first2=Lindsey B. |last3=Zhang |first3=Qian |last4=Michailidis |first4=Eleftherios |last5=Hoffmann |first5=Hans-Heinrich |last6=Zhang |first6=Yu |last7=Dorgham |first7=Karim |last8=Philippot |first8=Quentin |last9=Rosain |first9=Jérémie |last10=Béziat |first10=Vivien |last11=Manry |first11=Jérémy |last12=Shaw |first12=Elana |last13=Haljasmägi |first13=Liis |last14=Peterson |first14=Pärt |last15=Lorenzo |first15=Lazaro |date=2020-10-23 |title=Autoantibodies against type I IFNs in patients with life-threatening COVID-19 |url=https://www.science.org/doi/10.1126/science.abd4585 |journal=Science |language=en |volume=370 |issue=6515 |doi=10.1126/science.abd4585 |issn=0036-8075 |pmc=7857397 |pmid=32972996}}

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 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 }}

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.{{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 }}

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.{{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 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 |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 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}}

Some cytokines have been developed into 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}}

• 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{{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 }}

{{Div col}}

• Adipokines
• Apoptosis
• Cytokine redundancy
• Cytokine release syndrome
• Cytokine secretion assay
• ELISA assays
• Myokine
• Signal transduction
• Thymic stromal lymphopoietin
• Virokine

{{Div col end}}

{{reflist|30em}}

{{Commons category|Cytokines}}

• [http://www.cytokinesignalling.com Cytokine Signalling Forum]
• [http://www.elisakits.co.uk/immunology-cytokines/cytokine-tutorial Cytokine Tutorial]
• [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)]
• {{EMedicine|article|1162437|Reperfusion Injury in Stroke}}

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Category:Immunology