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

The Regenerating gene (REG) I alpha 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 I alpha axis and examined the mechanism of regulation of REG I alpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG I alpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG I alpha 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 I alpha 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 I alpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG I alpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG I alpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG I alpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between 142 and 134 in the REG I alpha promoter region. REG I alpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.