Abstract
Nitric oxide (NO) derived from the inducible NO synthase (iNOS) is an important and complex mediator of inflammation in the intestine. Wnt-inducible secreted protein (WISP)-1 (CCN4), a member of the connective tissue growth factor family, is involved in tissue repair. We sought to determine the relationship between iNOS and WISP-1 in colitis. By analyzing human colonic biopsy samples, we showed that the expression of mRNA for both iNOS and WISP-1 was significantly higher in ulcerative colitis samples compared with control tissue. The upregulation of WISP-1 was positively correlated with iNOS expression in two models of colitis, induced by intrarectal trinitrobenzenesulfonic acid (TNBS) or occurring spontaneously in IL-10 deficient mice. Loss of iNOS, studied using iNOS(-/-) mice in both TNBS-induced and IL-10(-/-) colitis models, significantly attenuated the colitis-related WISP-1 increase. In human colonic epithelial cell lines, the NO donor, DETA-NONOate, elevated WISP-1 mRNA and protein expression through a beta-catenin and CREB-dependent, but Wnt-1-independent, pathway. In addition, NO-induced WISP-1 directly induced secretion of soluble collagen in colonic fibroblast cells. NO increases WISP-1 expression both in vitro and in vivo, suggesting a new role for iNOS and NO in colitis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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CCN Intercellular Signaling Proteins
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Caco-2 Cells
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Cell Line, Tumor
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Colitis / chemically induced
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Colitis / genetics
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Colitis / metabolism
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Colitis, Ulcerative / genetics
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Colitis, Ulcerative / metabolism
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Colitis, Ulcerative / pathology*
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dose-Response Relationship, Drug
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Gene Expression / drug effects
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HT29 Cells
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Humans
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Interleukin-10 / deficiency
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Interleukin-10 / genetics
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Knockout
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Nitric Oxide / metabolism*
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Nitroso Compounds / pharmacology
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Trinitrobenzenesulfonic Acid
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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CCN Intercellular Signaling Proteins
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CCN4 protein, human
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CCN4 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Intracellular Signaling Peptides and Proteins
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Nitric Oxide Donors
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Nitroso Compounds
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Oncogene Proteins
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Proto-Oncogene Proteins
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beta Catenin
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Interleukin-10
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2,2'-(hydroxynitrosohydrazono)bis-ethanamine
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Nitric Oxide
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Trinitrobenzenesulfonic Acid
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Nitric Oxide Synthase Type II