Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2α

Moss, Alan C.; Anton, Pauline; Savidge, Tar; Newman, Paul; Cheifetz, Adam S.; Gay, Jerome; Paraschos, Sophia; Winter, Michael Weinstein; Moyer, Mary P.; Karalis, Katia; Kokkotou, Efi; Pothoulakis, Charalabos
September 2007
Gut;Sep2007, Vol. 56 Issue 9, p1210
Academic Journal
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 EUSA, 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 (HTT 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 CRHR20α receptor and may play an important role in the pathophysiology of colitis in humans.


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