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,¶
* Gastrointestinal Neuropeptide Center, Gastroenterology Division, Beth Israel Deaconess Medical Center, Boston, MA 02215;
Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital,
Department of Pathology, Boston University Medical Center, Boston, MA;
Department of Molecular Biology, Neurocrine Biosciences Inc., San Diego, CA; and
¶ Division of Endocrinology, Children’s Hospital, Harvard Medical School, Boston MA
Corticotropin-releasing hormone (CRH) and urocortins (Ucn) bind with various affinities to two G-protein-coupled receptors, CRHR1 and CRHR2, which are expressed in brain and in peripheral tissues, including immune cells. CRHR2-deficient mice display anxiety-like behavior, hypersensitivity to stress, altered feeding behavior and metabolism, and cardiovascular abnormalities. However, the phenotype of these mice in inflammatory responses has not been determined. In the present study we found that compared with wild-type CRHR2-null mice developed substantially reduced intestinal inflammation and had lower intestinal mRNA expression of the potent chemoattractants keratinocyte chemokine and monocyte chemoattractant protein 1 following intraluminal exposure to Clostridium difficile toxin A, a potent enterotoxin that mediates antibiotic-associated diarrhea and colitis in humans. This effect was recapitulated by administration of astressin 2B, a selective CRHR2 antagonist, before toxin A exposure. Moreover, Ab array analysis revealed reduced expression of several inflammatory chemokines, including keratinocyte chemokine and monocyte chemoattractant protein 1 in toxin A-exposed mice pretreated with astressin 2B. Real-time RT-PCR of wild-type mouse intestine showed that only UcnII, but not other Ucn, was significantly up-regulated by ileal administration of toxin A at 4 h compared with buffer exposure. We also found that human colonic epithelial HT-29 cells express CRHR2
mRNA, whereas expression of 
and 
spliced variants was minimal. Moreover, treatment of HT-29 cells with UcnII, which binds exclusively to CRHR2, stimulated expression of IL-8 and monocyte chemoattractant protein 1. Taken together, these results provide direct evidence that CRHR2 mediates intestinal inflammatory responses via release of proinflammatory mediators at the colonocyte level.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research Grants P0-1 DK 33506, DK 38458, and DK 47977 from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Charalabos Pothoulakis, Beth Israel Deaconess Medical Center, Harvard Medical School, Division of Gastroenterology, Dana 601, 330 Brookline Avenue, Boston, MA 02215. E-mail address: cpothoul{at}bidmc.harvard.edu
3 Abbreviations used in this paper: CRH, corticotropin-releasing hormone; Ucn, urocortin; CRHR, CRH receptor; KC, keratinocyte chemokine; MPO, myeloperoxidase; MCP-1, monocyte chemoattractant protein 1; AU, arbitrary units; WT, wild type; KO, knockout.
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