Mechanisms underlying the anti-inflammatory actions of central corticotropin-releasing factor.
Immune activation of hypothalamic corticotropin-releasing factor (CRF) provides a negative feedback mechanism to modulate peripheral inflammatory responses. We investigated whether central CRF attenuates endothelial expression of intercellular adhesion molecule 1 (ICAM-1) and leukocyte recruitment during endotoxemia in rats and determined its mechanisms of action. As measured by intravital microscopy, lipopolysaccharide (LPS) induced a dose-dependent increase in leukocyte rolling, adhesion, and emigration in mesenteric venules, which was associated with upregulation of endothelial ICAM-1 expression. Intracisternal injection of CRF abrogated both the increased expression of ICAM-1 and leukocyte recruitment. Intravenous injection of the specific CRF receptor antagonist astressin did not modify leukocyte-endothelial cell interactions induced by a high dose of LPS but enhanced leukocyte adhesion induced by a low dose. Blockade of endogenous glucocorticoids but not alpha-melanocyte-stimulating hormone (alpha-MSH) receptors reversed the inhibitory action of CRF on leukocyte-endothelial cell interactions during endotoxemia. In conclusion, cerebral CRF blunts endothelial upregulation of ICAM-1 and attenuates the recruitment of leukocytes during endotoxemia. The anti-inflammatory effects of CRF are mediated by adrenocortical activation and additional mechanisms independent of alpha-MSH.
Casadevall
M
M
Gastroenterology Department, Institut Clínic de Malalties Digestives, Hospital Clínic, University of Barcelona, 08035 Barcelona, Spain.
Saperas
E
E
Panés
J
J
Salas
A
A
Anderson
D C
DC
Malagelada
J R
JR
Piqué
J M
JM
D000315:Adrenalectomy; D000818:Animals; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007278:Injections, Spinal; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*; D007421:Intestine, Small / Q000098:blood supply; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018715:Microscopy, Video / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013152:Splanchnic Circulation / Q000502:physiology*; D014699:Venules / Q000502:physiology*
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; D018799:Intercellular Adhesion Molecule-1; C104416:astressin; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone