Murine Guanylate Cyclase C Regulates Colonic Injury and Inflammation

Guanylate cyclase C (GUCY2C or GC-C) and its ligands, guanylin (GUCA2A or Gn) and uroguanylin (GUCA2B or Ugn), are expressed in intestinal epithelial cells and regulate ion secretion, intestinal barrier function, and epithelial monolayer homeostasis via cGMP-dependent signaling pathways. The aim of this study was to determine whether GC-C and its ligands direct the course of intestinal inflammation. In this article, we show that dextran sodium sulfate (DSS)-induced clinical disease and histological damage to the colonic mucosa were significantly less severe in GC-C-/- mice and moderately reduced in Gn(-/-) animals. Relative to wildtype controls, GC-C-/- and Gn(-/-) mice had reduced apoptosis and increased proliferation of intestinal epithelial cells during DSS colitis. Basal and DSS-induced production of resistin-like molecule beta (RELM beta) was substantially diminished in GC-C-/- mice. RELMb is thought to stimulate cytokine production in macrophages in this disease model and, consistent with this, TNF-alpha and IFN-gamma production was minimal in GC-C-/- animals. RELMb and cytokine levels were similar to wild-type in Gn(-/-) mice, however. Colonic instillation of recombinant RELMb by enema into GC-C-/- mice restores sensitivity to DSS-mediated mucosal injury. These findings demonstrate a novel role for GC-C signaling in facilitating mucosal wounding and inflammation, and further suggest that this may be mediated, in part, through control of RELMb production. The Journal of Immunology, 2011, 186: 7205-7214.