Cytokine

Cytokines (Greek cyto-, cell; and -kinos, movement) are a category of signaling molecules that, like hormones and neurotransmitters, are used extensively in cellular communication. They are proteins, peptides or glycoproteins. The term cytokine encompasses a large and diverse family of polypeptide regulators that are produced widely throughout the body by cells of diverse embryological origin.^[1]

Historically, the term "cytokine" has been used to refer to the immunomodulating agents (interleukins, inferferons, etc.). Conflicting data exists about what is termed a cytokine and what is not. More research is needed in the area of defining a cytokine and defining the properties a peptide must have in order to be considered a cytokine.

The action of cytokines may be autocrine, paracrine, and endocrine. Cytokines are critical to the development and functioning of both the innate and adaptive immune response, although not limited to just the immune system. They are often secreted by immune cells that have encountered a pathogen, thereby activating and recruiting further immune cells to increase the system's response to the pathogen. Cytokines are also involved in several developmental processes during embryogenesis.

Effects

Each cytokine is an STD 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.

Generalization of functions is not possible with cytokines. Nonetheless, their actions may be grouped as:

• autocrine, if the cytokine acts on the cell that secretes it.
• paracrine, if the target is restricted to the immediate vicinity of a cytokine's secretion.
• endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).

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.

Overstimulation of cytokines can trigger a dangerous syndrome known as a cytokine storm; this may have been the cause of severe adverse events during a clinical trial of TGN1412.

Nomenclature

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.

• The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally leukocytes. It is now used largely for designation of newer cytokine molecules discovered every day and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
• The term chemokine refers to a specific class of cytokines that mediates chemoattraction (chemotaxis) between cells.

IL-8 (interleukin-8) is the only chemokine originally named an interleukin.

Classification

Structural

Structural homology 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 - Member cytokines have three-dimensional structures with four bundles of α-helices. This family in turn is divided into three sub-families:
  1. the IL-2 subfamily
  2. the interferon (IFN) subfamily
  3. the IL-10 subfamily.
  The first of these three subfamilies is the largest. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (THPO). Also, four α-helix bundle cytokines can be grouped into long-chain and short-chain cytokines.
• the IL-1 family, which primarily includes IL-1 and IL-18
• 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 divides immunological cytokines into those that enhance cytokine responses, type 1 ( IFN-γ, TGF-β etc.), and type 2 (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.

Cytokine 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 pleiomorphism 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.
• Haemopoietic 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 (TNF).
• 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 (CXCR4 and CCR5), also belong to this family.

Cysteine-knot cytokines

Members of the transforming growth factor beta superfamily belong to this group, including TGF-β1, TGF-β2 and TGF-β3.

References

Further reading

• Gallin J, Snyderman R (eds). Inflammation: Basic Principles and Clinical Correlates. 3rd edition, Philadelphia, Lippincott William and Wilkins, 1999.
• Janeway CA et al. (eds). Immunobiology. The immune system in Health and Disease, 4th edition, New York, Garland, 1999.
• Roitt I et al. (eds.) Immunology. 5th edition, London, Mosby, 2002.
• Prlic M, Bevan MJ (March 2006). "Immunology. An antibody paradox, resolved". Science (journal) 311 (5769): 1875–6. doi:10.1126/science.1126030. PMID 16574856. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=16574856. 

See also

• Adipokines
• Apoptosis
• Cytokine secretion assay
• Cytokine storm
• ELISA assays
• ELISPOT assays
• Granulocyte-colony stimulating factor
• Signal transduction

External links

• Cytokine Tutorial
• Cell Interactions: Cytokines
• Reperfusion Injury in Stroke.
• Cytokines Online Pathfinder Encyclopaedia