title: The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease.
abstract: OBJECTIVE
  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 (GUCY2C/Gucy2c) and its endogenous ligands guanylin (GN/GUCA2A/Guca2a) and uroguanylin (UGN/GUCA2B/Guca2b) 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 GUCA2A and GUCY2C and expression of inflammatory cytokines (IL1A, IL1B, TNFA and IFNG) were conducted. Additionally, expression of transcription factors for GUCA2A and GUCY2C, and the GC-C signaling pathway, were examined.
  
  
  METHODS
  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 in situ hybridization (ISH).
  
  
  RESULTS
  GUCA2A/Guca2a, GUCA2B, GUCY2C/Gucy2c, 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 GUCA2A and GUCY2C negatively correlated to expression of inflammatory cytokines. IHC and ISH confirmed microarray results for GUCA2A/Guca2a and GUCY2C/Gucy2c in inflamed samples. We identified a highly significant positive correlation between the expression of the transcription factor caudal type homeobox 2 (CDX2) and the expression of the downstream target gene GUCY2C.
  
  
  CONCLUSIONS
  GUCA2A, GUCA2B and GUCY2C as well as several steps of the GC-C signaling pathway are down-regulated in IBD. This may have implications in IBD pathogenesis.
authors.affiliation: Department of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim University Hospital , Trondheim , Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Brenna
authors.forename: Torunn
authors.initials: T
authors.lastname: Bruland
authors.forename: Marianne W
authors.initials: MW
authors.lastname: Furnes
authors.forename: Atle van Beelen
authors.initials: Av
authors.lastname: Granlund
authors.forename: Ignat
authors.initials: I
authors.lastname: Drozdov
authors.forename: Johanna
authors.initials: J
authors.lastname: Emgård
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brønstad
authors.forename: Mark
authors.initials: M
authors.lastname: Kidd
authors.forename: Arne K
authors.initials: AK
authors.lastname: Sandvik
authors.forename: Björn I
authors.initials: BI
authors.lastname: Gustafsson
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D016022:Case-Control Studies; D003113:Colonoscopy / Q000379:methods; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051381:Rats; D012016:Reference Values; D015398:Signal Transduction / Q000235:genetics
chemical_list: D006162:Guanylate Cyclase
keywords: cyclic GMP; guanylate cyclase-C; guanylin; inflammatory bowel disease; uroguanylin