Cytokine Antagonists

A number of proteins that inhibit the biological activity of cytokines have been reported. These proteins act in one of two ways: either they bind directly to a cytokine receptor but fail to activate the cell, or they bind directly to a cytokine, inhibiting its activity. The best-characterized inhibitor is the IL-1 receptor antagonist (IL-1Ra), which binds to the IL-1 receptor but has no activity. Binding of IL-1Ra to the IL-1 receptor blocks binding of both IL-1a and IL-1 p, thus accounting for its antagonistic properties. Production of IL-1Ra has been thought by some to play a role in regulating the intensity of the inflammatory response. It has been cloned and is currently being investigated as a potential treatment for chronic inflammatory diseases.

Cytokine inhibitors are found in the bloodstream and extracellular fluid. These soluble antagonists arise from enzymatic cleavage of the extracellular domain of cytokine receptors. Among the soluble cytokine receptors that have been detected are those for IL-2, -4, -6, and -7, IFN-7 and -a, TNF-p, and LIF. Of these, the soluble IL-2 receptor (sIL-2R), which is

TABLE 12-3

Viral mimics of cytokine and cytokine receptors

Virus

Leporipoxvirus

(a myxoma virus) Several poxviruses Vaccinia, smallpox virus Epstein-Barr Human herpesvirus-8

Cytomegalovirus

Product

Soluble IFN-7 receptor

Soluble IFN-7 receptor

Soluble IL-1 ß receptor

IL-10 homolog

IL-6 homolog; also homologs of the chemokines MIP-I and MIP-II

Three different chemokine receptor homologs, one of which binds three different soluble chemokines (RANTES, MCP-1, and MIP-1«)

Cytokine secretion and principal functions of mouse Th1 and Th2 subsets

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