IL-6 and Crohn's disease.
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 Crohn's 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 alpha, IL-1beta, and interferon gamma mRNA without affecting the production of transforming growth factor beta, IL-10, and IL-4. Moreover, the treatment displayed therapeutic efficacy against established colitis through the induction of lamina propria T-cell apoptosis. These results strongly suggest that specific targeting of IL-6/sIL-6R pathway will be a promising new approach for the treatment of Crohn's disease, and the clinical trial of humanized anti-IL-6R mAb has been carried out.
Ito
Hiroaki
H
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. hiroito@imed3.med.osaka-u.ac.jp
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000503:physiopathology; D003424:Crohn Disease / Q000503:physiopathology*; D016207:Cytokines / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6