Corticotropin-releasing factor regulates TLR4 expression in the colon and protects mice from colitis.
OBJECTIVE
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.
Chaniotou
Zoi
Z
Developmental Biology Section, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Giannogonas
Panagiotis
P
Theoharis
Stamatis
S
Teli
Thalia
T
Gay
Jerome
J
Savidge
Tor
T
Koutmani
Yassemi
Y
Brugni
James
J
Kokkotou
Efi
E
Pothoulakis
Charalabos
C
Karalis
Katia P
KP
D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000401:mortality; D003106:Colon / Q000276:immunology*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009017:Morbidity; D013312:Stress, Physiological / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003346:Corticotropin-Releasing Hormone; D016264:Dextran Sulfate