INTERLEUKIN-6 - STRUCTURE-FUNCTION-RELATIONSHIPS

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a centra l role in host defense due to its wide range of immune and hematopoiet ic activities and its potent ability to induce the acute phase respons e. Overexpression of IL-6 has been implicated in the pathology of a nu mber of diseases including multiple myeloma, rheumatoid arthritis, Cas tleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. I L-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1 and cilia ry neurotrophic factor. Like the other members of this family, IL-6 in duces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Id entification of the regions of IL-6 that are involved in the interacti ons with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affinity specific receptor, the IL-6 receptor, and the h igh-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to th e mechanism of action of the other members of the IL-6 family of cytok ines.