Proinflammatory cytokines down-regulate intestinal selenoprotein P biosynthesis via NOS2 induction

Selenoprotein P (SeP). serving as selenium transporter and exracellular antioxidant, is assumed to have a protective role in the gastrointestinal tract, which is particularly susceptible to oxidative damage. Decreased SeP mRNA levels have been found in colon cancer: however, information on the control of intestinal SeP biosynthesis is scarce We analyzed SeP biosynthesis in human intestinal epithelial Caco-2 cells subject to differentiation [Tom crypt- to villous-like enterocytes In the course of Caco-2 cell differentiation, SeP mRNA expression and secretion increased concomitant with three regulators of SeP transcription hepatocyte nuclear factor-4 alpha, forkhead box class O1 a. and peroxisomal proliferator-activated receptor-gamma coactivator la Treatment of differentiated Caco-2 cells with the proinflammatory cytokines IL-1 beta,TNF-alpha, and IFN-gamma caused a down-regulation of SeP biosynthesis, resulting from induction of nitric oxide synthase 2 These observations were corroborated by decreased SeP mRNA levels in the colon of dextran sodium sulfate-treated mice, an animal model of experimental colitis We conclude that inflammation of the intestinal mucosa causes a decline in locally produced selenoprotein P in the colon that eventually may contribute to the emergence of inflammatory bowel disease-related colorectal cancer (C) 2010 Elsevier Inc All rights reserved