Nitric oxide increases Wnt-induced secreted protein-1 (WISP-1/CCN4) expression and function in colitis

J Mol Med (Berl). 2009 Apr;87(4):435-45. doi: 10.1007/s00109-009-0445-4. Epub 2009 Feb 24.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • CCN Intercellular Signaling Proteins
  • CCN4 protein, human
  • CCN4 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Intracellular Signaling Peptides and Proteins
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • beta Catenin
  • Interleukin-10
  • 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
  • Nitric Oxide
  • Trinitrobenzenesulfonic Acid
  • Nitric Oxide Synthase Type II