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Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2α
  1. Alan C Moss (amoss{at}bidmc.harvard.edu)
  1. Harvard Medical School, United States
    1. Pauline Anton
    1. Harvard Medical School, United States
      1. Tor Savidge
      1. Harvard Medical School, United States
        1. Paul Newman
        1. Harvard Medical School, United States
          1. Adam S Cheifetz (acheifet{at}bidmc.harvard.edu)
          1. Harvard Medical School, United States
            1. Jerome Gay
            1. Harvard Medical School, United States
              1. Sophia Paraschos
              1. Harvard Medical School, United States
                1. Michael Weinstein Winter
                1. Harvard Medical School, United States
                  1. Mary P Moyer
                  1. Incell Corporation, United States
                    1. Katia Karalis
                    1. Harvard Medical School, United States
                      1. Efi Kokkotou (ekokkoto{at}bidmc.harvard.edu)
                      1. Harvard Medical School, United States
                        1. Charalabos Pothoulakis (cpothoul{at}bidmc.harvard.edu)
                        1. Harvard Medical School, United States

                          Abstract

                          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 synthesized in the intestine, but its role in human intestinal inflammation is largely unknown.

                          Methods: We measured responses of human colonic epithelial cells expressing CRHR2 to stimulation by UcnII using ELISA, Western blot analysis, real time RT-CPR, and 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 Crohns and ulcerative colitis, and in human intestinal xenografts after exposure to Clostridium difficile toxin A.

                          Results: We report 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 TNFα. Stimulation of non-transformed NCM460 colonocytes overexpressing CRHR2α receptor with UcnII resulted in a time- and concentration-dependent increase in IL-8 production. UcnII stimulation also led to activation of the transcription factor NF-κB and MAP kinase in these cells, as evidenced by degradation of IκBαand phosphorylation of the p65 subunit of NF-κB and 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 CRHR2αreceptor and may play an important role in the pathophysiology of colitis in humans.

                          • colitis
                          • corticotropin-releasing hormone receptor 2
                          • neuropeptides
                          • urocortin II

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