IL-6 and Crohns Disease

Hiroaki      Ito

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine with central roles in immune regulation, inflammation, hematopoiesis, and oncogenesis. Its biological activities are shared by IL-6-family of cytokines such as leukemia inhibitory factor and oncostatin M. When IL-6 binds to IL-6R, the IL-6 / IL-6R complex then associates with gp130, the common signal transducer of cytokines related to IL-6. IL-6R does not have to be expressed on the cell surface for IL-6 signaling because soluble form of IL-6R (sIL-6R) can bind to IL-6 and function through gp130. Increased levels of IL-6 and sIL-6R have been demonstrated in both serum and intestinal tissues of the patients with active Crohns disease. In animal model studies, anti-IL-6R monoclonal antibody (mAb) successfully prevented intestinal inflammation and systemic wasting disease by suppressing adhesion molecule expression by vascular endothelium. It also reduced colonic expression of tumor necrosis factor α, IL-1β, and interferon γ mRNA without affecting the production of transforming growth factor β, IL-10, and IL-4. Moreover, the treatment displayed therapeutic efficacy against established colitis through the induction of lamina propria Tcell apoptosis. These results strongly suggest that specific targeting of IL-6 / sIL-6R pathway will be a promising new approach for the treatment of Crohns disease, and the clinical trial of humanized anti-IL-6R mAb has been carried out.

Keywords: interleukin-6, soluble interleukin-6 receptor, gp130, monoclonal antibody, crohns disease, adhesion molecule, t cell, apoptosis