Important Role for STAT3 in the Pathogenesis of Crohn's Disease

克隆氏病和溃疡性结肠炎患者血清IL-6和可溶性IL-6受体(sIL-6R)水平升高。我们研究了阻断IL-6信号转导的抗IL-6R单抗对实验性结肠炎的治疗潜力。将同源正常小鼠的CD4+CD45RBHigh T细胞转移给SCID小鼠，从T细胞转移后开始，每周一次注射大鼠抗小鼠IL-6R单抗。以大鼠免疫球蛋白为对照。抗IL-6R单抗可显著抑制对照组小鼠体重减轻、腹泻、组织性结肠炎等临床症状。明显抑制ICAM-1、VCAM-1等血管内皮细胞黏附分子的表达，降低肠道CD4+T细胞和巨噬细胞的数量。抗IL-6R单抗可降低肠组织中干扰素-γ、IL-1β和肿瘤坏死因子-α的表达，但不影响IL-10和β的表达。肠道中诱导型一氧化氮合酶的表达也显著减少。诱导型一氧化氮合酶被称为粘膜屏障破坏者。原位末端标记法显示，抗IL-6R单抗可促进T细胞的凋亡。因此，抗IL-6R单抗不仅通过减少黏附分子在血管内皮细胞中的表达，而且还通过抑制STAT3依赖的抗凋亡基因来减少T细胞的侵袭。我们还检测了抗IL-6R单抗在溃疡性结肠炎模型和DSS诱导的结肠炎中的作用。DSS前腹腔注射抗IL-6R单抗可减轻结肠炎的严重程度，但不影响STAT3的磷酸化。P-STAT3的定位由肠上皮细胞向单核细胞转移，提示激活STAT3的信号转导可能与肠粘膜的修复有关。表皮生长因子被认为是粘膜愈合过程中激活STAT3的因素之一。

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.