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Lab Invest. 2010 Mar;90(3):496-505. doi: 10.1038/labinvest.2009.147. Epub 2010 Jan 11.

Involvement of the IL-22/REG Ialpha axis in ulcerative colitis.

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Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan.


The Regenerating gene (REG) Ialpha protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ialpha axis and examined the mechanism of regulation of REG Ialpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ialpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ialpha protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ialpha promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ialpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ialpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ialpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ialpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between -142 and -134 in the REG Ialpha promoter region. REG Ialpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.

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