Cytokine: Difference between revisions

Content deleted Content added

Inline

Revision as of 11:47, 14 February 2006

Cytokines are soluble proteinaceous substances produced by a wide variety of haemopoietic and non-haemopoietic cell types, and are critical to the functioning of both innate and adaptive immune responses. Apart from their role in the development and functioning of the immune system, and their aberrant modes of secretion in a variety of immunological, inflammatory and infectious diseases, cytokines are also involved in several developmental processes during human embryogenesis.

Effects

The effects of cytokines are mediated by their binding to a specific cell-surface receptor and the subsequent initiation of various intracellular signalling cascades that produce a wide variety of effects on the functioning of the cell. This may include the upregulation and/or downregulation of several genes and their transcription factors, that result in production of other cytokines, or increase in the number of surface receptors for other molecules, or suppress their own effect by feedback inhibition.

Accordingly, cytokines are characterised by considerable redundancy, in that many cytokines can share similar functions. Similarly, cytokines are also pleotropic, in that they are capable of acting on many different cell types. Of course, this would be an anticipated corollary if one considers the simple fact that a given cell type may express receptors for more than one cytokine, or that many different tissues can express receptors for the same cytokine.

Generalisation of functions is not possible with cytokines; nonetheless, their actions may be comfortably grouped as

autocrine, if the cytokine acts on the cell which secretes it,
paracrine, if the action is restricted to the immediate vicinity of a cytokine's secretion, and
endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma) and mediates its effects on different tissues.

Nomenclature

Cytokines have been variously named as lymphokines, interleukins and chemokines, based on their presumed function, and their cell of secretion or target of action. In view of the fact that cytokines are characterised by considerable redundancy and pleotropism, such a distinction has, with few exceptions, become largely obsolete.

The term interleukin was initially used by researchers for those cytokines whose presumed targets were prinicipally leukocytes. The term chemokine referred to a specific class of cytokines which mediated chemoattraction (chemotaxis) between cells. The latter term alone has been retained (see below); interleukins are now used largely for designation of newer cytokine molecules discovered everyday, and have little significance attached to their presumed function.

Of note, IL-8 (interleukin-8) is the only chemokine that was originally named an interleukin.

Classification

Cytokines have now been classified into four different types based on structural homology, which has been partly able to separate cytokines which do not demonstrate a considerable degree of redundancy.

Four α-helix bundle family, the three dimensional structures of whose members have four bundles of α-helices (a type of protein folding). This family inturn is divided into three sub-families, the IL-2 subfamily, the interferon (INF) subfamily and the IL-10 subfamily. The first of these three subfamilies is the largest, and contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (THPO).
IL-1 family, which primarily includes IL-1 and IL-18.
IL-17 family, which is yet to be completely characterised. However, it is known that they have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.
Chemokines

A more clinically and experimentally useful classification divides immunological cytokines into those that promote the proliferation and functioning of helper T-cells type 1 (example, IL-1, INF-γ etc.) and helper T-cells type 2 (IL-4, IL-10, IL-13, TGF-β etc.) respectively. Remarkably, the cytokines which belong to one of these sub-sets tend to inhibit the effects of their counterparts - a tendency under intensive study for their possible role in the pathogenesis of autoimmune disorders.

Cytokine Receptors

In recent years, the cytokine receptors have come to demand the attention of several 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 pleomorphism 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 X-linked form of Severe Combined Immunodeficiency (X-SCID).
Interferon (type 2) family, whose members are receptors for INF 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 CD 30, besides the ligands on which the family is named (TNF).
Seven transmembrane helix family, the ubiquitous receptor type in animal kingdom. All G-protein coupled receptors (for hormones and neurotransmitters) belong to this family. Importantly, the chemokine receptors, two of which act as binding proteins for the HIV virus (CXCR 4 and CCR 5), also belong to this family.

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.

External links

@@ Line 31: / Line 31: @@
 In recent years, the cytokine receptors have come to demand the attention of several 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 pleomorphism 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 pharmacological targets.)
+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 found throughout all 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.
+* '''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 [[X-linked form of Severe Combined Immunodeficiency]] (X-SCID).
 * '''Interferon (type 2) family''', whose members are receptors for INF β and γ.