Cytokine

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(Redirected from
Recombinant cytokine
)
Not to be confused with Cytokinin, a class of plant hormones promoting cell division.

3D medical animation still showing secretion of cytokines

Cytokines are a broad and loose category of small

endocrine signaling as immunomodulating agents
.

Cytokines include

tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology). 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.[2][3] 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. They are different from hormones, 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 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'.

Discovery

Interferon-alpha, an

interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator.[5] Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.[6][7]

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".[8] In 1974, pathologist Stanley Cohen, M.D. (not to be confused with the 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.[9] Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.[10]

Difference from hormones

Classic

TNF-α.[11] In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas.[12] The current terminology refers to cytokines as immunomodulating agents
.

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some

endocrine as a pyrogen
. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

A scalable vector graphic of signal transduction pathways
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.

Nomenclature

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
    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.

Classification

Structural

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:

  1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO).[13] They can be grouped into long-chain and short-chain cytokines by topology.[14] Some members share the common gamma chain as part of their receptor.[15]
  2. the interferon (IFN) subfamily.
  3. the IL-10 subfamily.
  • The
    IL-1 family, which primarily includes IL-1 and IL-18
    .
  • The
    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 cause cytotoxic effects.

Functional

A classification that proves more useful in clinical and experimental practice outside of

autoimmune disorders. Several inflammatory cytokines are induced by oxidative stress.[16][17] The fact that cytokines themselves trigger the release of other cytokines [18][19][20] 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.[21] There are both pro-inflammatory and anti-inflammatory
cytokines that regulate this pathway.

Receptors

Main article: 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.

Cellular effects

Each cytokine has a matching

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

PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[23] 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.[24]

Roles in health and disease

Cytokines are involved in several developmental processes during

hemorrhagic stroke.[29] 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.[30]

A 2019 review was inconclusive as to whether cytokines play any definitive role in

ME/CFS.[31]

Adverse effects

Adverse effects of cytokines have been linked to many disease states and conditions ranging from

TGF-β.[35]
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.[36]

Over-secretion of cytokines can trigger a dangerous

COVID-19 infections.[41]

Medical use as drugs

Some cytokines have been developed into

protein therapeutics using recombinant DNA technology.[42] Recombinant cytokines being used as drugs as of 2014 include:[43]

See also

Notes

  1. ^ 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)
  2. ^ Chen explains the regulatory activity of LIF in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner." (719)

References

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External links

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