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Background & Aims Defects in the colonic innate immune response have been associated with inflammatory bowel disease (IBD). Corticotropin-releasing hormone (CRH, or corticotropin-releasing factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and TLR4. We investigated the role of CRF in an innate immunitydependent mouse model of IBD. Methods Crh-/- and wild-type (Crh+/+) mice, which are glucocorticoid insufficient, were given dextran sodium sulfate in their drinking water to induce colitis; in some experiments, mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators. Results Crh-/- mice had more colonic inflammation than Crh+/+ mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the proinflammatory factors interleukin-12 and prostaglandin E2 were increased in the Crh-/- mice. Colons of Crh -/- mice expressed lower levels of Tlr4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh-/- mice from developing severe colitis. Crh-/- mice were unable to recover from acute colitis, as indicated by their increased death rate. Conclusions Mice deficient in CRF down-regulate TLR4 and are more susceptible to dextran sodium sulfateinduced colitis. CRF has anti-inflammatory effects in innate immunitydependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD. © 2010 AGA Institute. |
