Wang Lixin, Walia Baljit, Evans John, Gewirtz Andrew T, Merlin Didier, Sitaraman Shanthi V
Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA 30322, USA.
J Immunol. 2003 Sep 15;171(6):3194-201. doi: 10.4049/jimmunol.171.6.3194.
IL-6 is a potent proinflammatory cytokine that has been shown to play an important role in the pathogenesis of inflammatory bowel disease (IBD). It is classically known to activate gene expression via the STAT-3 pathway. Given the crucial role of IL-6 in the pathogenesis of chronic intestinal inflammation, it is not known whether IL-6 activates NF-kappaB, a central mediator of intestinal inflammation. The model intestinal epithelial cell line, Caco2-BBE, was used to study IL-6 signaling and to analyze whether suppressor of cytokine signaling 3 (SOCS-3) proteins play a role in the negative regulation of IL-6 signaling. We show that IL-6 receptors are present in intestinal epithelia in a polarized fashion. Basolateral IL-6 and, to a lesser extent, apical IL-6 induces the activation of the NF-kappaB pathway. Basolateral IL-6 stimulation results in a maximal induction of NF-kappaB activation and NF-kappaB nuclear translocation at 2 h. IL-6 induces polarized expression of ICAM-1, an adhesion molecule shown to be important in the neutrophil-epithelial interactions in IBD. Using various deletion constructs of ICAM-1 promoter, we show that ICAM-1 induction by IL-6 requires the activation of NF-kappaB. We also demonstrate that overexpression of SOCS-3, a protein known to inhibit STAT activation in response to IL-6, down-regulates IL-6-induced NF-kappaB activation and ICAM-1 expression. In summary, we demonstrate the activation of NF-kappaB by IL-6 in intestinal epithelia and the down-regulation of NF-kappaB induction by SOCS-3. These data may have mechanistic and therapeutic implications in diseases such as IBD and rheumatoid arthritis in which IL-6 plays an important role in the pathogenesis.
白细胞介素-6（IL-6）是一种强效促炎细胞因子，已被证明在炎症性肠病（IBD）的发病机制中起重要作用。传统上已知它通过信号转导和转录激活因子3（STAT-3）途径激活基因表达。鉴于IL-6在慢性肠道炎症发病机制中的关键作用，目前尚不清楚IL-6是否激活核因子κB（NF-κB），后者是肠道炎症的核心介质。利用模型肠上皮细胞系Caco2-BBE研究IL-6信号传导，并分析细胞因子信号传导抑制因子3（SOCS-3）蛋白是否在IL-6信号的负调控中发挥作用。我们发现IL-6受体以极化方式存在于肠上皮中。基底外侧的IL-6以及程度较轻的顶端IL-6可诱导NF-κB途径的激活。基底外侧IL-6刺激在2小时时导致NF-κB激活和NF-κB核转位的最大诱导。IL-6诱导细胞间黏附分子-1（ICAM-1）的极化表达，ICAM-1是一种在IBD中性粒细胞与上皮细胞相互作用中起重要作用的黏附分子。使用ICAM-1启动子的各种缺失构建体，我们发现IL-6诱导ICAM-1需要NF-κB的激活。我们还证明，SOCS-3的过表达（一种已知可抑制对IL-6反应的STAT激活的蛋白）可下调IL-6诱导的NF-κB激活和ICAM-1表达。总之，我们证明了IL-6在肠上皮中激活NF-κB以及SOCS-3对NF-κB诱导的下调作用。这些数据可能对IBD和类风湿性关节炎等疾病具有机制和治疗意义，其中IL-6在发病机制中起重要作用。
