Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor

Alan C. Moss, Pauline Anton, Tor Savidge, Paul Newman, Adam S. Cheifelz, Jerome Gay, Sophia Paraschos, Michael Weinstein Winter, Mary P. Moyer, Katia Karalis, Efi Kokkotou, Charalabos Pothoulakis

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Background/Aims: Urocortin II (UcnII) is a neuropeptide that binds with high affinity to the corticotropin-releasing hormone receptor 2 (CRHR2) in peripheral tissues. UcnII is synthesised in the intestine, but its role in human intestinal inflammation is largely unknown. Methods: Responses of human colonic epithelial cells expressing CRHR2 to stimulation by UcnII were measured using ELISA, western blot analysis, real-time reverse transcription-PCR (RT-PCR) and interleukin (IL)8 promoter activity. Expression levels of CRHR2 and UcnII in human colitis were determined by immunofluorescence and real-time RT-PCR in mucosal biopsies from patients with Crohn's and ulcerative colitis, and in human intestinal xenografts after exposure to Clostridium difficile toxin A. Results: It is reported here that expression of CRHR2 mRNA and protein in human colonic epithelial cells (HT-29) are increased by exposure to C difficile toxin A or tumour necrosis factor (TNF)α. Stimulation of non-transformed NCM460 colonocytes overexpressing CRHR2α receptor with UcnII resulted in a time- and concentration-dependent increase in IL8 production. UcnII stimulation also led to activation of nuclear factor-κB (NF-κB) and mitogen-acivated protein (MAP) kinase in these cells, as evidenced by degradation of IκBα and phosphorylation of the p65 subunit of NF-κB and extracellularly regulated kinase (ERK) 1/2. Furthermore, expression of UcnII and CRHR2 mRNA was increased in mucosal samples of patients with inflammatory bowel disease, and after exposure of human intestinal xenografts to C difficile toxin A. Conclusions: These results suggest that UcnII has pro-inflammatory effects in human intestinal cells via the CRHR2α receptor and may play an important role in the pathophysiology of colitis in humans.

Original languageEnglish (US)
Pages (from-to)1210-1217
Number of pages8
Issue number9
StatePublished - Sep 2007
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology


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