The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease. (October 2015)

• Record Type: Journal Article
• Authors: Brenna, Øystein; Bruland, Torunn; Furnes, Marianne W.; Granlund, Atle van Beelen; Drozdov, Ignat; Emgård, Johanna; Brønstad, Gunnar; Kidd, Mark; Sandvik, Arne K.; Gustafsson, Björn I.
• Is Part Of: Scandinavian journal of gastroenterology. Volume 50:Number 10(2015)
• Page Start: 1241
• Page End: 1252
• Publication Date: 2015-10
• Subjects: Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; 616.33
• DOI: 10.3109/00365521.2015.1038849
• Languages: English
• ISSNs: 0036-5521

Abstract

<abstract> <title>Abstract</title> <p> <bold> <italic>Objective.</italic> </bold> Activation of membrane receptor guanylate cyclase-C (GC-C) is implicated in gastrointestinal fluid and electrolyte balance, preservation of intestinal barrier integrity, anti-trophic effects and inhibition of pain sensation. To evaluate GC-C signaling, we examined the regulation of GC-C (<italic>GUCY2C</italic>/<italic>Gucy2c</italic>) and its endogenous ligands guanylin (GN/<italic>GUCA2A</italic>/<italic>Guca2a</italic>) and uroguanylin (UGN/<italic>GUCA2B</italic>/<italic>Guca2b</italic>) in colonic Crohn's disease (CD), ulcerative colitis (UC) and in rats with 2, 4, 6-Trinitrobenzene sulphonic acid (TNBS) colitis. Correlation analyses between expression of <italic>GUCA2A</italic> and <italic>GUCY2C</italic> and expression of inflammatory cytokines (<italic>IL1A, </italic><italic>IL1B, </italic><italic>TNFA</italic> and <italic>IFNG</italic>) were conducted. Additionally, expression of transcription factors for <italic>GUCA2A</italic> and <italic>GUCY2C, </italic> and the GC-C signaling pathway, were examined. <bold><italic>Material and methods.</italic></bold> Biopsies from active UC/CD, un-inflamed UC/CD and healthy controls, and inflamed and healthy rat colon were investigated with gene expression microarray, immunohistochemistry (IHC) and <italic>in situ</italic> hybridization (ISH). <bold><italic>Results.</italic></bold><italic>GUCA2A</italic>/<italic>Guca2a, </italic><italic>GUCA2B, </italic><italic>GUCY2C</italic>/<italic>Gucy2c, </italic> transcription factors, as well as several cyclic guanosine-3′, 5′-monophosphate downstream mediators were all significantly down-regulated in both inflamed colonic inflammatory bowel disease (IBD) mucosa and TNBS colitis. Expression of <italic>GUCA2A</italic> and <italic>GUCY2C</italic> negatively correlated to expression of inflammatory cytokines. IHC and ISH confirmed microarray results for <italic>GUCA2A</italic>/<italic>Guca2a</italic> and <italic>GUCY2C</italic>/<italic>Gucy2c</italic> in inflamed samples. We identified a highly significant positive correlation between the expression of the transcription factor caudal type homeobox 2 (<italic>CDX2</italic>) and the expression of the downstream target gene <italic>GUCY2C.</italic><bold><italic>Conclusions.</italic> GUCA2A, </bold><italic>GUCA2B</italic> and <italic>GUCY2C</italic> as well as several steps of the GC-C signaling pathway are down-regulated in IBD. This may have implications in IBD pathogenesis.</p> </abstract>