结肠炎
促炎细胞因子
TLR4型
先天免疫系统
炎症
内分泌学
糖皮质激素
促肾上腺皮质激素释放激素
炎症性肠病
内科学
免疫系统
免疫学
医学
受体
生物
疾病
作者
Zoi Chaniotou,Panagiotis Giannogonas,Stamatis Theoharis,Thalia Teli,Tor Savidge,Yassemi Koutmani,James Brugni,Efi Kokkotou,Charalabos Pothoulakis,Katia Karalis
标识
DOI:10.1053/j.gastro.2010.08.024
摘要
Background & AimsDefects 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.MethodsCrh−/− 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.ResultsCrh−/− 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.ConclusionsMice 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. 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.
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