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1 Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
2 Department of Pharmacology, Graduate School of Medicine, Osaka City University, Osaka, Japan
* To whom correspondence should be addressed. E-mail: andoh{at}belle.shiga-med.ac.jp.
Interleukin-11 (IL-11) inhibits the activation of nuclear factor (NF)-
B, and induces the Th2 polarization of CD4+ T cells. The clinical utility of IL-11 is being investigated in Crohn's disease. However, physiologic 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 blotting. The activating protein (AP)-1-DNA binding activity was evaluated by electrophoretic gel mobility shift assays (EMSA). IL-11 secretion was induced by IL-1
and transforming growth factor (TGF)-1. These were also observed at the mRNA level. The EMSAs demonstrated that both IL-1 and TGF-1 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-1- and TGF-1-induced IL-11 mRNA expression. IL-1 and TGF-1 induced an activation of ERK p42/44 and p38 MAP kinases, and the MAP kinase inhibitors (SB202190, PD098059 and U0216) significantly reduced the IL-1- and TGF-1-induced IL-11 secretion. The up-regulation of IL-11 mRNA by IL-1- and TGF-1 was also mediated by a p38 MAP-kinase-mediated mRNA stabilization. The combination of IL-1 and TGF-1 additively enhanced IL-11 secretion. Intestinal SEMFs secreted IL-11 in response to IL-1- and TGF-1. Mucosal IL-11 secretion might be an important as an anti-inflammatory response in the pathogenesis of intestinal inflammation.
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