IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases

Abstract

A series of studies have revealed that IL-6 has pleiotropic activity in various cells and that its deregulated expression is responsible for the development of multiple autoimmune inflammatory diseases. A humanized antibody against the IL-6 receptor, tocilizumab, has exhibited outstanding therapeutic efficacy against rheumatoid arthritis, juvenile idiopathic arthritis, Castleman’s disease, and other autoimmune inflammatory diseases, leading to its clinical use for treatment of several diseases. These findings indicate that overproduction of IL-6 is responsible for the pathogenesis of autoimmune inflammatory diseases, in which an imbalance between Th17 cells and regulatory T cells and autoantibodies play central roles. Recent studies have suggested that IL-6 blockade therapy can rectify these underlying immunological abnormalities in autoimmunity. However, the causes of deregulated IL-6 production in these diseases remain unknown. A novel IL-6-regulating molecule, Arid5a, specifically stabilizes IL-6 mRNA and sustains its overproduction; thus, Arid5a plays an important role in promoting inflammation and autoimmune diseases. Indeed, in Arid5a-knockout mice, experimental autoimmune encephalomyelitis does not develop, and lipopolysaccharide stimulation does not induce elevated expression of IL-6. Arid5a can counteract the destabilizing effect of a regulatory RNase, Regnase-1, on IL-6 mRNA; Regnase-1 knockout mice spontaneously develop various fatal autoimmune diseases. Further analyses of these RNA-binding proteins as well as other regulatory molecules for IL-6 expression are expected to elucidate the molecular mechanisms underlying deregulated synthesis of IL-6, and facilitate investigations of the pathogenesis of specific diseases.