Proinflammatory cytokines down-regulate intestinal selenoprotein P biosynthesis via NOS2 induction.
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-4alpha, forkhead box class O1a, and peroxisomal proliferator-activated receptor-gamma coactivator 1alpha. Treatment of differentiated Caco-2 cells with the proinflammatory cytokines IL-1beta, 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.
Speckmann
Bodo
B
Institute for Biochemistry and Molecular Biology I, Heinrich-Heine University, D-40225 Düsseldorf, Germany.
Pinto
Antonio
A
Winter
Meike
M
Förster
Irmgard
I
Sies
Helmut
H
Steinbrenner
Holger
H
D000818:Animals; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051149:Selenoprotein P / Q000096:biosynthesis* / Q000235:genetics
D016207:Cytokines; D018836:Inflammation Mediators; D051149:Selenoprotein P; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II