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.

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.

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.

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.