| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Increased serum levels of IL-6 and soluble IL-6 receptor (sIL-6R) in the patients wifh Crohn's disease and ulcerative colitis has been reported. We examined therapeutic potential .of anti-IL-6R monoclonal antibody (mAb), which blocks signal transduction of IL-6, for experimental colitis. SCID mice transferred CD4+ CD45RBhigh T cells from congenic normal mice were treated with weekly intraperitoneal injection of rat anti-mouse IL-6R mAb starting just after T cell transfer. Rat IgG was given as control. Clinical symptoms such as body weight loss and diarrhea and histological colitis, which were observed in the control mice, remarkably suppressed by anti-IL-6R mAb treatment. The treatment strongly suppressed the expression of vascular endothelial adhesion molecules such as ICAM-1 and VCAM-1, and decreased the number of intestinal CD4+ T cells and macrophages. Anti-IL-6R mAb reduced intestinal expression of IFN-γ, IL-1β, and TNF-α mAb without affecting the expression of IL-10 and TGF-β. Intestinal expression of inducible nitric oxide synthase, which is known as mucosal barrier breaker, also remarkably decreased. Moreover, anti-IL-6R mAb increased T cell apoptosis as shown by TUNEL method. Therefore, anti-IL-6R mAb decreased T cell infiltration not only by reduction of adhesion molecule expression in the vascular endothelium but also by suppression of STAT3-dependent anti-apoptotic genes. We also examined the effect of anti-IL-6R mAb in ulcerative colitis model, DSS-induced colitis. Intraperitoneal administration of anti-IL-6R mAb prior to DSS reduced the severity of colitis, however, phosphorylation of STAT3 was not affected. Localization of phosphor-STAT3 shifted from intestinal mononuclear cells to epithelial cells, which suggested that signaling through the activation of STAT3 may be related to the healing of intestinal mucosa. Epidermal growth factor was supposed to be one of the factors which activate STAT3 in the mucosal healing process.
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