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

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• 作者：Bodo Speckmann ; Antonio Pinto ; Meike Winter ; Irmgard Fö ; rster ; Helmut Sies ; Holger Steinbrenner
• 关键词：NOS-2 ; Selenoprotein ; HNF-4α ; Caco-2 ; Colitis ; FoxO1a ; PGC-1α
• 刊名：Free Radical Biology and Medicine
• 出版年：2010
• 出版时间：1 September 2010
• 年：2010
• 卷：49
• 期：5
• 页码：777-785
• 全文大小：836 K

文摘

Selenoprotein P (SeP), serving as selenium transporter and extracellular 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 from 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-4α, forkhead box class O1a, and peroxisomal proliferator-activated receptor-γ coactivator 1α. Treatment of differentiated Caco-2 cells with the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ 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.