Corticotropin-releasing hormone deficiency is associated with reduced local inflammation in a mouse model of experimental colitis.
CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.
Gay
Jérôme
J
Division of Endocrinology, Children's Hospital, Boston, MA 02215, USA.
Kokkotou
Efi
E
O'Brien
Michael
M
Pothoulakis
Charalabos
C
Karalis
Katia P
KP
D000818:Animals; D000855:Anorexia / Q000097:blood / Q000235:genetics / Q000473:pathology; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D003346:Corticotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D015431:Weight Loss
D015850:Interleukin-6; D020738:Leptin; D014302:Trinitrobenzenesulfonic Acid; D003346:Corticotropin-Releasing Hormone