2-2--(hydroxynitrosohydrazono)bis-ethanamine and Colitis

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.

Topics: Animals; beta Catenin; Blotting, Western; Caco-2 Cells; CCN Intercellular Signaling Proteins; Cell Line, Tumor; Colitis; Colitis, Ulcerative; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Gene Expression; HT29 Cells; Humans; Interleukin-10; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type II; Nitroso Compounds; Oncogene Proteins; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Time Factors; Trinitrobenzenesulfonic Acid