Mechanisms underlying the ani-inflammatory actions of central corticotropin-releasing factor

Immune activation of hypothalamic corticotropin-releasing factor (CRF) prov ides a negative feedback mechanism to modulate peripheral inflammatory resp onses. We investigated whether central CRF attenuates endothelial expressio n of intercellular adhesion molecule 1 (ICAM-1) and leukocyte recruitment d uring endotoxemia in rats and determined its mechanisms of action. As measu red by intravital microscopy, lipopolysaccharide (LPS) induced a dose-depen dent increase in leukocyte rolling, adhesion, and emigration in mesenteric venules, which was associated with upregulation of endothelial ICAM-1 expre ssion. Intracisternal injection of CRF abrogated both the increased express ion of ICAM-1 and leukocyte recruitment. Intravenous injection of the speci fic CRF receptor antagonist astressin did not modify leukocyte-endothelial cell interactions induced by a high dose of LPS but enhanced leukocyte adhe sion induced by a low dose. Blockade of endogenous glucocorticoids but not alpha-melanocyte-stimulating hormone (alpha-MSH) receptors reversed the inh ibitory action of CRF on leukocyte-endothelial cell interactions during end otoxemia. In conclusion, cerebral CRF blunts endothelial upregulation of IC AM-1 and attenuates the recruitment of leukocytes during endotoxemia. The a nti-inflammatory effects of CRF are mediated by adrenocortical activation a nd additional mechanisms independent of alpha-MSH.