Cytokine

Cytokines are a group of proteins and peptides that are used in organisms as signaling compounds. These chemical signals are similar to hormones and neurotransmitters and are used to allow one cell to communicate with another. The cytokine family consists mainly of smaller water-soluble proteins and glycoproteins (proteins with an added sugar chain) with a mass of between 8 and 30 kDa. While hormones are released from specific organs into the blood and neurotransmitters are released by nerves, cytokines are released by many types of cells. They are particularly important in both innate and adaptive immune responses. Due to their central role in the immune system, cytokines are involved in a variety of immunological, inflammatory and infectious diseases. However, not all their functions are limited to the immune system, as they are also involved in several developmental processes during embryogenesis.

When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.

Cytokines are produced by a wide variety of cell types (both haemopoietic and non-haemopoietic) and can have effects on both nearby cells or throughout the organism. Sometimes these effects are strongly dependent on the presence of other chemicals and cytokines.

Effects

Each cytokine binds to a specific 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, in turn 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. Interestingly, 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 comfortably grouped as:

autocrine, if the cytokine acts on the cell that secretes it
paracrine, if the action 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) to affect different tissues.

Cytokines binding to antibodies paradoxically have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses and perhaps fewer side effects.

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 variously named as lymphokines, interleukins and chemokines, based on their presumed function, cell of secretion or target of action. Because cytokines are characterized 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 term chemokine refers to a specific class of cytokines that mediates chemoattraction (chemotaxis) between cells.

Of note, 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). Alternatively, four α-helix bundle cytokines can be grouped into long chain and short chain cytokines.
the IL-1 family - It primarily includes IL-1 and IL-18.
the IL-17 family - It has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.
Chemokines

Functional

A more clinically and experimentally useful classification divides immunological cytokines into those that promote the proliferation and functioning of helper T-cells, type 1 ( IFN-γ etc.) and type 2 (IL-4, IL-10, IL-13, TGF-β etc.), respectively.

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. This tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders.

Cytokine receptors

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 have 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 are now of the opinion 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. (It must be noted that such a classification, though seemingly cumbersome, provides with 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.
Tumour Necrosis Factor (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. It is important to note that 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

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.
Science Vol. 311 No. 5769, pp. 1875 - 1876, 31 March 2006 DOI: 10.1126/science.1126030

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