Corticotropin-Releasing Factor Regulates TLR4 Expression in the Colon and Protects Mice From Colitis

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 immunity–dependent 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 E 2 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 sulfate–induced colitis. CRF has anti-inflammatory effects in innate immunity–dependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD.