Interferon-alpha, aninterferon type I, was identified in 1957 as a protein that interfered with viral replication.[5] The activity of interferon-gamma (the sole member of theinterferon type II class) was described in 1965; this was the first identifiedlymphocyte-derived mediator.[6]Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.[7][8]
In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines".[9] In 1974, pathologist Stanley Cohen, M.D. (not to be confused with theNobel laureate named Stanley Cohen, who was a PhD biochemist;nor with the MD geneticistStanley Norman Cohen) published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine.[10] In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.[11]
Classichormones circulate inaqueous solution in nanomolar (10-9 M)concentrations that usually vary by less than oneorder of magnitude. In contrast, some cytokines (such asIL-6) circulate in picomolar (10-12 M) concentrations that can increase up to 1,000 times duringtrauma orinfection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually allnucleated cells, but especially endo/epithelial cells and residentmacrophages (many near the interface with the external environment) are potent producers ofIL-1,IL-6, andTNF-α.[12] In contrast, classic hormones, such asinsulin, are secreted from discreteglands such as thepancreas.[13] The current terminology refers to cytokines asimmunomodulating agents.
A contributing factor to the difficulty of distinguishing cytokines from hormones is that someimmunomodulating effects of cytokines are systemic (i.e., affecting the whole organism) rather than local. For instance, to accurately utilize hormone terminology, cytokines may beautocrine orparacrine in nature, andchemotaxis,chemokinesis andendocrine as apyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.
Cytokines typically activatesecond 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.
Cytokines have been classed aslymphokines,interleukins, andchemokines, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy andpleiotropism, such distinctions, allowing for exceptions, are obsolete.
The terminterleukin was initially used by researchers for those cytokines whose presumed targets are principallywhite 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 byT-helper 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 fourα-helices. This family, in turn, is divided into three sub-families:
theIL-2 subfamily. This is the largest family. It contains several non-immunological cytokines includingerythropoietin (EPO) andthrombopoietin (TPO).[14] They can be grouped intolong-chain andshort-chain cytokines by topology.[15] Some members share thecommon gamma chain as part of their receptor.[16]
TheIL-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 ofstructural biology divides immunological cytokines into those that enhancecellular immune responses, type 1 (TNFα, IFN-γ, etc.), and those that enhanceantibody 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 thepathogenesis ofautoimmune disorders. Severalinflammatory cytokines are induced byoxidative stress.[17][18] The fact that cytokines themselves trigger the release of other cytokines[19][20][21] and lead to increased oxidative stress makes them important in chronicinflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.[22] There are both pro-inflammatory andanti-inflammatory cytokines that regulate this[clarification needed] pathway.
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.
Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellularamino-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 ofSevere 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 acysteine-rich common extracellular binding domain, and includes several other non-cytokineligands likeCD40,CD27 andCD30, besides the ligands on which the family is named.
Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.[23]
Each cytokine has a matchingcell-surface receptor. Subsequentcascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of severalgenes and theirtranscription 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 byfeedback 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 toantibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.
It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of[24] T-cell expansion and function by up-regulatingPD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[24] Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespreadpapular eruptions.[25]
Cytokines are involved in several developmental processes duringembryonic development.[26][nb 1][27][nb 2] Cytokines are released from theblastocyst, and are also expressed in theendometrium, and have critical roles in the stages ofzona hatching, andimplantation.[28] Cytokines are crucial for fighting off infections and in other immune responses.[29] However, they can become dysregulated and pathological ininflammation, trauma,sepsis,[29] andhemorrhagic stroke.[30] Dysregulated cytokine secretion in the aged population can lead toinflammaging, and render these individuals more vulnerable to age-related diseases like neurodegenerative diseases and type 2 diabetes.[31]
A 2019 review was inconclusive as to whether cytokines play any definitive role inME/CFS.[32]
A 2024 study found a positive correlation between plasma interleukinIL-2 and fatigue in patients with type 1narcolepsy.[33]
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.[34]
Adverse effects of cytokines have been linked to many disease states and conditions ranging fromschizophrenia,major depression[35] andAlzheimer's disease[36] tocancer.[37] 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 ofTreg cells.Foxp3 polymorphism (rs3761548) might be involved in cancer progression likegastric cancer through influencingTregs function and the secretion of immunomodulatory cytokines such asIL-10,IL-35, andTGF-β.[38] Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated byadhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity.[39]
Over-secretion of cytokines can trigger a dangerouscytokine storm syndrome. Cytokine storms may have been the cause of severe adverse events during a clinical trial ofTGN1412. Cytokine storms are also suspected to have been the main cause of death in the1918 "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 inacute pancreatitis. Cytokines are integral and implicated in all angles of the cascade, resulting in thesystemic inflammatory response syndrome andmulti-organ failure associated with this intra-abdominal catastrophe.[40] In theCOVID-19 pandemic, some deaths fromCOVID-19 have been attributable to cytokine release storms.[41][42][43] Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation inCOVID-19 infections.[44]
^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 ofLIF 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)
^Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT (October 1969). ""Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation".Nature.224 (5214):38–42.Bibcode:1969Natur.224...38D.doi:10.1038/224038a0.PMID5822903.S2CID4172811.
^Cohen S, Bigazzi PE, Yoshida T (April 1974). "Commentary. Similarities of T cell function in cell-mediated immunity and antibody production".Cell. Immunol.12 (1):150–159.doi:10.1016/0008-8749(74)90066-5.PMID4156495.
^Vlahopoulos S, Boldogh I, Casola A, Brasier AR (September 1999). "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation".Blood.94 (6):1878–1879.doi:10.1182/blood.V94.6.1878.418k03_1878_1889.PMID10477716.S2CID25974629.
^David F, Farley J, Huang H, Lavoie JP, Laverty S (April 2007). "Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes".Vet Surg.36 (3):221–227.doi:10.1111/j.1532-950X.2007.00253.x.PMID17461946.
^Yang Q, Wu Q, Zhan Q, Deng L, Ding Y, Wang F, et al. (February 2024). "Association between cytokines and fatigue in patients with type 1 narcolepsy".Journal of Clinical Neuroscience.120 (1): 102.doi:10.1016/j.jocn.2024.01.007.
^Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease".Biol. Psychiatry.68 (10):930–941.doi:10.1016/j.biopsych.2010.06.012.PMID20692646.S2CID6544784.
^Makhija R, Kingsnorth AN (2002). "Cytokine storm in acute pancreatitis".Journal of Hepato-Biliary-Pancreatic Surgery.9 (4):401–410.doi:10.1007/s005340200049.PMID12483260.
