Abstract

Proinflammatory cytokines have been demonstrated to play a crucial role in the pathogenesis and physiopathology of various chronic inflammatory conditions including Crohn's disease (CD). Among these cytokines, interleukin-6 (IL-6) must be especially important because increased serum concentrations of acute phase proteins, reduced level of serum albumin, and remarkable thrombocytosis are all well-explained by the increased level of IL-6. Moreover, IL-6 is capable of stimulating even IL-6 receptor (IL-6R) negative cells such as vascular endothelial cells when complexed to soluble form of IL-6R (sIL-6R), and serum level of IL-6 as well as sIL-6R has been demonstrated to increase during inflammation. To investigate the therapeutic potential of IL-6 signaling blockade for CD, anti-IL-6R monoclonal antibody (mAb) was introduced to various murine models of colitis. Anti-IL-6R mAb successfully prevented wasting disease and the development of macroscopic and histological lesions. It suppressed the accumulation of ICAM-1 positive and Mac-1 positive cells in the lamina propria (LP) and the expression of ICAM-1 and VCAM-1 by vascular endothelial cells. Expansion of colonic and splenic CD4(+) T cells was reduced as well as the colonic expression of tumor necrosis factor alpha (TNF-alpha), IL-1beta, and interferon gamma (IFN-gamma) mRNA without affecting the production of transforming growth factor beta (TGF-beta), IL-10, and IL-4 mRNA. The treatment also suppressed established colitis by inducing LP 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 CD, and the clinical trial of humanized anti-IL-6R mAb is now under way.