Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways

Abstract

IL-11 inhibits the activation of NF-κB and induces the Th2 polarization of CD4+T cells. The clinical utility of IL-11 is being investigated in Crohn's disease. However, physiological secretion of IL-11 in the intestine remains unclear. In this study, we investigated IL-11 secretion in human intestinal subepithelial myofibroblasts (SEMFs). Intestinal SEMFs were isolated from the human colonic mucosa. IL-11 secretion and mRNA expression were determined by ELISA and Northern blot analysis. The activating protein (AP)-1-DNA binding activity was evaluated by EMSA. IL-11 secretion was induced by IL-1β and transforming growth factor (TGF)-β1. These were also observed at the mRNA level. The EMSAs demonstrated that both IL-1β and TGF-β1 induced AP-1 activation within 2 h after stimulation, and a blockade of AP-1 activation by the recombinant adenovirus containing a dominant negative c-Jun markedly reduced the IL-1β- and TGF-β1-induced IL-11 mRNA expression. IL-1β and TGF-β1 induced an activation of ERK p42/44 and p38 MAP kinases, and the MAP kinase inhibitors (SB-202190, PD-98059, and U-0216) significantly reduced the IL-1β- and TGF-β1-induced IL-11 secretion. The upregulation of IL-11 mRNA by IL-1β- and TGF-β1 was also mediated by a p38 MAP kinase-mediated mRNA stabilization. The combination of IL-1β and TGF-β1 additively enhanced IL-11 secretion. Intestinal SEMFs secreted IL-11 in response to IL-1β- and TGF-β1. Mucosal IL-11 secretion might be important as an anti-inflammatory response in the pathogenesis of intestinal inflammation.