Cytokine Receptor

Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine, monokine, chemokine, and interleukin.

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Background


The term 'cytokine' was first introduced in the mid-1970s. It was applied to polypeptide growth factors controlling the differentiation and regulation of cells of the immune system. Cytokines are a diverse group of regulatory proteins or glycoproteins whose classification remains somewhat confusing (Figure 1). The interferons (IFNs) and interleukins (ILs) represented the major polypeptide families classified as cytokines at that time. Additional classification terms were also introduced, including lymphokines [cytokines such as interleukin-2 (IL-2) and interferon-γ (IFN-γ), produced by lymphocytes] and monokines [cytokines such as tumour necrosis factor-α (TNF-α) produced by monocytes]. However, classification on the basis of producing cell types also proved inappropriate, as most cytokines are produced by a range of cell types, e.g. both lymphocytes and monocytes produce IFN-α.

The major proteins protein families that constitute the cytokine group of regulatory molecules

Figure 1: The major proteins protein families that constitute the cytokine group of regulatory molecules

During the 1980s, rapid developments in the areas of recombinant DNA technology and monoclonal antibody technology contributed to a greater depth of understanding of cytokine biology:

1.genetic engineering allowed production of large quantities of most cytokines. These could be used for structural and functional studies of the cytokine itself, and its receptor;

2.analysis of cytokine genes established the exact evolutionary relationships between these molecules;

3.detection of cytokine mRNA and cytokine receptor mRNA allowed identification of the full range of sources and target cells of individual cytokines;

4. hybridoma technology facilitated development of immunoassays capable of detecting and quantifying cytokines;

5.inhibition of cytokine activity in vivo by administration of monoclonal antibodies, and more recently by gene knockout studies, continues to elucidate the physiological and pathophysiological effect of various cytokines.

Recombinant DNA technology has also facilitated detailed study of cytokine receptors. Based upon amino acid sequence homology, receptors are usually classified as belonging to one of six known superfamilies (Figure 2). Individual members of any one superfamily characteristically display 20-50% homology. Conserved amino acids normally occur in discrete bands or clusters, which usually correspond to a discrete domain in the receptor. Most receptors exhibit multiple domains. In some cases a single receptor may contain domains characteristic of two or more superfamilies, e.g. the IL-6 receptor contains domains characteristic of both the haematopoietic and immunoglobulin superfamilies, making it a member of both.

Some cytokine receptors are composed of a single transmembrane polypeptide (e.g. receptors for IL-8, IL-9 and IL-10). Many contain two polypeptide components (including IL-3, IL-4 and IL-5 receptors), while a few contain three or more polypeptide components, e.g. the IL-2 receptor contains three polypeptide chains. In some instances a single cytokine may be capable of initiating signal transduction by binding two or more distinct receptors, e.g. IL-1 has two distinct receptors (types I and II), both of which are transmembrane glycoproteins.

The cytokine receptor superfamilies

Figure 2: The cytokine receptor superfamilies

In many cases where a receptor consists of multiple polypeptides, one of those polypeptides (which will be unique to that receptor) will interact directly with the ligand. The additional polypeptide(s), responsible for initiation of signal transduction, may be shared by a number of receptors. This explains the pleiotrophy exhibited by many cytokines. Some cytokine receptors can directly initiate signal transduction upon binding of ligand. In other cases additional elements are involved. For many receptors the exact intracellular events triggered upon ligand binding remain unelucidated. However, the molecular details of signal transduction pathways for others are now understood.

Reference:

Walsh, G. (2013). Biopharmaceuticals: biochemistry and biotechnology. John Wiley & Sons.