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Cytokine

Cytokines are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communication. While hormones are secreted from specific organs to the blood, and neurotransmitters are related to neural activity, the cytokines are a more diverse class of compounds in terms of origin and purpose. They are produced by a wide variety of hematopoietic and non-hematopoietic cell types and can have autocrine, paracrine and endocrine effects, sometimes strongly dependent on the presence of other chemicals. The cytokine family consists mainly of smaller, water-soluble proteins and glycoproteins with a mass between 8 and 30 kDa.

Cytokines are critical to the development and functioning of both the innate and adaptive immune response. 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 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, 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:

  the IL-2 subfamily

  the interferon (IFN) subfamily

  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

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 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. 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

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