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Corticotropin-Releasing Hormone Deficiency Is Associated with Reduced Local Inflammation in a Mouse Model of Experimental Colitis

Division of Endocrinology (J.G., K.P.K.), Children’s Hospital, Gastrointestinal Neuropeptide Center (E.K., C.P.), Gastroenterology Division, Beth Israel Deaconess Medical Center, and Department of Pediatrics and Nutrition (E.K., C.P., K.P.K.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Pathology (M.O.), Boston University Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Katia Karalis, BRFAA, 4 Soranou Efessiou, Papagou, 115 27 Athens, Greece. E-mail: kkarali{at}bioacademy.gr.

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.