CYTOKINE RECEPTOR AGONISTS

CYTOKINE RECEPTOR AGONISTS act at one or more of the extremely diverse group of sites recognizing cytokine mediators. Cytokines are peptide inflammatory mediators belonging to a superfamily with a number of classes. Included are the interferons, the interleukins, tumour necrosis factor and mammalian growth factors, and also a number of further factors. The cytokines are mainly produced by macrophages and lymphocytes, and also by other leucocytes, flbroblasts and endothelial cells. They act by activating recruiting and regulating processes and cells within the inflammatory and immune system, and differentiation and multiplications of cells in the repair process. The term lymphokine was formerly applied to cytokines produced by lymphocytes. The chemokines are a subset of cytokines that are chemotactic to leucocytes.

Cytokine receptor studies are still evolving, but several subfamilies of receptors and putative ligands have been proposed. Currently, over 30 receptors have been identified, and some of these have been cloned. Given this state of flux, only an outline account of these receptors is given.

Chemokine family. The mediators are divided into four subclasses according to chemical characteristics of the ligands, namely the number or positions of cyteine residues, as follows: CC chemokines; CXC chemokines; CX3C chemokine; C chemokines. These chemokines act at receptors largely named after the peptides themselves, and include CCCR1-8 and CXR1-4. Chemokines recognized include MIP-1α; MIP-1β; MCP-1; MCP-2; MCP-3: MCP-4; MIP-5; RANTES; LCR1; leukotactin-1; eotaxin, eotaxin-1; and some other chemokines.

Interleukin-1 receptor family. The mediators themselves include IL-1α, IL-1β, and the receptors include at least two types; IL-1R1 and IR-1RII.

Tumour necrosis factor (TNF) receptor family. The mediators themselves include TNF (α & β) and lymphotoxin a, and there are at least four receptor subtypes.

Haematopoetin receptor family. The mediators themselves include IL-2 through to IL-15, with one receptor each at which they are preferred ligands; also there are GM-CSF and G-CSF and other mediators.

Receptor coupling mechanisms. A number are G-protein coupled (Gi/o), but others involve JAK/STAT, i.e. signalling depends upon receptor association with Janus kinases (JAKs), which couple ligand binding to tyrosine phosphorylation of signalling proteins recruited to the receptor complex.

Individual mediators: A number of cytokines with immunomodulatory, antiviral and anticancer activities are discussed elsewhere (see immunomodulators). These include interferon α (INF-alpha; actually a family of peptides), interferon β (INF-beta), interferon γ (INF-γ), interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor and the colony-stimulating factors granulocyte-macrophage-colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF) (TNFα & β). Some other cytokines mentoned above are; macrophage inhibitory protein 1 (MIP-1α & MIP-1β, MIP-5 etc.), monocyte chemotactic proteins (MCP-2, MCP-3 etc.), RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted); leukotactin-1; eotaxin, eotaxin-1.

Clearly, there is enormous therapeutic potential in the manipulation of cell-signalling via the cytokines, as well as better understanding pathophysiology as their roles unfold.