Nitric oxide increases Wnt-induced secreted protein-1 (WISP-1/CCN4) expression and function in 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.
Wang
Hongying
H
University of Calgary, AB, Canada. hongyingwang@cicams.ac.cn
Zhang
Rui
R
Wen
Shoubin
S
McCafferty
Donna-Marie
DM
Beck
Paul L
PL
MacNaughton
Wallace K
WK
D000818:Animals; D015153:Blotting, Western; D055511:CCN Intercellular Signaling Proteins; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D016753:Interleukin-10; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D052247:Nitric Oxide Synthase Type II