Cytokine

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3D medical animation still showing secretion of cytokines

Cytokines (Template:IPAc-en)<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} </ref> are a broad and loose category of small proteins (~5–25 kDa<ref>Template:Cite book</ref>) 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 receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology)Template:Cn. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.<ref>Template:Cite book</ref><ref>Template:Cite book</ref> They act through cell surface receptors and are especially important in the immune system; cytokines modulate the balance between humoral and 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.Cytokines are also released in lower concentrations than hormones. Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.

The word comes from the ancient Greek language: cyto, from Greek κύτος, kytos, 'cavity, cell' + kines, from Greek κίνησις, kinēsis, 'movement'.

DiscoveryEdit

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication.<ref name="pmid13465720">Template:Cite journal</ref> 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.<ref name="pmid17838106">Template:Cite journal</ref> Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.<ref name="pmid5938421">Template:Cite journal</ref><ref name="pmid5229858">Template:Cite journal</ref>

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".<ref name="pmid5822903">Template:Cite journal</ref> 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.<ref name="pmid4156495">Template:Cite journal</ref> In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.<ref>Template:Cite journal</ref>

Difference from hormonesEdit

Classic hormones circulate in aqueous solution in nanomolar (10^-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^-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.<ref>Template:Cite journal</ref> In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas.<ref name="Cannon2000">Template:Cite journal</ref> 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.svg

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.

NomenclatureEdit

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.

ClassificationEdit

StructuralEdit

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

the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO).<ref>Template:Cite journal</ref> They can be grouped into long-chain and short-chain cytokines by topology.<ref>Template:Cite journal</ref> Some members share the common gamma chain as part of their receptor.<ref>Template:Cite journal</ref>
the interferon (IFN) subfamily.
the IL-10 subfamily.

The IL-1 family, which primarily includes IL-1 and IL-18.
The cysteine knot cytokines (Template:UniProt) 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.

FunctionalEdit

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.<ref name="pmid10477716">Template:Cite journal</ref><ref name="pmid17461946">Template:Cite journal</ref> The fact that cytokines themselves trigger the release of other cytokines<ref name="pmid24185478">Template:Cite journal</ref><ref name="pmid11922866">Template:Cite journal</ref><ref name="pmid16191192">Template:Cite journal</ref> 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.<ref name="pmid17426506">Template:Cite journal</ref> There are both pro-inflammatory and anti-inflammatory cytokines that regulate thisTemplate:Clarify pathway.

ReceptorsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.Template:Citation needed
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.<ref name="pmid19575028">Template:Cite journal</ref>

Cellular effectsEdit

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<ref name="Said2010">Template:Cite journal</ref> 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.<ref name="Said2010" /> 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.<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Template:ISBN.Template:Page needed</ref>

Roles in health and diseaseEdit

Cytokines are involved in several developmental processes during embryonic development.<ref name="pmid11600175">Template:Cite journal</ref><ref group="nb">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)</ref><ref name="pmid10521116">Template:Cite journal</ref><ref group="nb">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)</ref> 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.<ref name="Seshagiri">Template:Cite journal</ref> Cytokines are crucial for fighting off infections and in other immune responses.<ref name="pmid10936147">Template:Cite journal</ref> However, they can become dysregulated and pathological in inflammation, trauma, sepsis,<ref name="pmid10936147" /> and hemorrhagic stroke.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

A 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.<ref>Template:Cite journal</ref>

A 2024 study found a positive correlation between plasma interleukin IL-2 and fatigue in patients with type 1 narcolepsy.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

In March 2025, researchers in Saudi Arabia showed that those who received mRNA COVID vaccines elevated cytokine levels one year after the vaccination, and the immune responses differed between gender and age groups. The vaccination resulted in significant increases in inflammatory markers: interferon gamma(INF gamma, p=0.005), tumor necrosis factor alpha(TNF alpha, p<0.001), interleukin-6(IL6, p=0.003), monocyte chemoattractants(MCP1, p=0.03, MCP3, p=0.001) and so on. Bigger changes in IL6, IL4 and TNF alpha were observed by men than women -- and significant changes in epidermal growth factor(EGF), IL6, MCP1, and TNF alpha were seen in adults compared to adolescents. The study suggested that the elevation was linked to the persistent production of spike protein and highly inflammatory nature of mRNA-nanoparticles.<ref>Template:Cite journal </ref>

Adverse effectsEdit

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression<ref name="pmid20015486">Template:Cite journal</ref> and Alzheimer's disease<ref name="pmid20692646">Template:Cite journal</ref> to cancer.<ref name="pmid11239407">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="pmid26119834">Template:Cite journal</ref>

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.<ref name="pmid12483260">Template:Cite journal</ref> In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms.<ref name="covid-1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="covid-2">Template:Cite journal</ref><ref name="covid-3">Template:Cite journal</ref> Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections.<ref>Template:Cite book</ref>

Medical use as drugsEdit

Some cytokines have been developed into protein therapeutics using recombinant DNA technology.<ref>Template:Cite journal</ref> Recombinant cytokines being used as drugs as of 2014 include:<ref>Template:Cite book</ref>