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Cytokines (Greek:Cyto from Greek "κύτταρο" kyttaro "cell" + Kines from Greek "κίνηση" kinisi "movement") are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines can also be involved in autocrine signaling. Cytokines include chemokines, interferons, interleukins, lymphokines, tumour necrosis factor but generally not hormones or growth factors (despite some terminologic overlap). 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.[1][2][3]
They act through 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.[3]
They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in much lower concentrations and hormones tend to be made by specific kinds of cells.
They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.
Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication.[4] 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.[4] Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.[4]
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". As scientists learned more, it was understood that these proteins and others were part of a broader class of proteins involved in self-defense, and should be called "cytokines".[4]
Classic hormones circulate 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-fold 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.[5] In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas).[6] As of 2008, the current terminology refers to cytokines as immunomodulating agents. However, more research is needed in this area of defining cytokines and hormones.
Part of the difficulty with distinguishing cytokines from hormones is that some of the immunomodulating effects of cytokines are systemic rather than local. For instance, to use hormone terminology, the action of cytokines may be autocrine or paracrine in chemotaxis or chemokinesis and endocrine as a pyrogen. Further, as molecules, cytokines are not limited to their immunomodulatory role.
Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.
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:
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 (IFN-γ, TNFα, etc.), and type 2 (TGF-β, IL-4, IL-10, IL-13, etc.), which favor antibody responses.
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.[7][8] The fact that cytokines themselves trigger the release of other cytokines[9][10][11] 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).
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.
Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signalling 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.
Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of[13] 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.[13]
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.[14]
Cytokines are often involved in several developmental processes during embryogenesis.[15][nb 1][16][nb 2]
Cytokines are crucial for fighting off infections and in other immune responses.[17] However, they can become dysregulated and pathological in inflammation, trauma, and sepsis.[17]
Adverse effects of cytokines have been linked to many disease states and conditions ranging from
Plasma levels of various cytokines may give information on the presence, or even predictive value of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis,[27] as well as immunomodulatory effects of foods or drugs.[28] In addition, elevated levels of IL-7, an important cytokine involved in T cell homeostasis, have been detected in the plasma of HIV-infected patients.[29]
Some cytokines have been developed into protein therapeutics using recombinant DNA technology.[23] Recombinant cytokines being used as drugs as of 2014 include:[24]
[22]
Endocrine system, Signal transduction, Notch signaling pathway, Cancer, Bacteria
Elisa, Protein, Immune system, Gene, Cancer
Gene expression, Metabolism, Apoptosis, Growth factor, Cancer
Tyrosine kinase, Cytokine, Gene, Janus kinase 1, Janus kinase 2
Evolution, Cytokine, Bone morphogenetic protein, Angiogenesis, Immune system
Medicine, Science, Psychiatry, Cancer, Allergy
Pfam, Rank, Interferon, Carbon, Hydrogen
Immune system, Antibody, Thymus, Immunology, Macrophages