Cerebrovascular cyclooxygenase-1 expression, regulation, and role in hypothalamic-pituitary-adrenal axis activation by inflammatory stimuli.
Systemic injection of lipopolysaccharide (LPS) is a widely used model of immune/inflammatory challenge, which can invoke a host of CNS responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis. Inducible vascular prostaglandin E(2) (PGE(2)) synthesis by endothelial (ECs) and/or perivascular cells (PVCs) (a macrophage-derived vascular cell type) is implicated in the engagement of HPA and other CNS responses, by virtue of their capacity to express cyclooxygenase-2 (COX-2) and microsomal PGE(2) synthase-1. Evidence from genetic and pharmacologic studies also supports a role for the constitutively expressed COX-1 in inflammation-induced activation of the HPA axis, although histochemical evidence to support relevant localization(s) and regulation of COX-1 expression is lacking. The present experiments fill this void in showing that COX-1 immunoreactivity (IR) and mRNA are detectable in identified PVCs and parenchymal microglia under basal conditions and is robustly expressed in these and ECs 1-3 h after intravenous injection of LPS (2 microg/kg). Confocal and electron microscopic analyses indicate distinct cellular/subcellular localizations of COX-1-IR in the three cell types. Interestingly, COX-1 expression is enhanced in ECs of brain PVC-depleted rats, supporting an anti-inflammatory role of the latter cell type. Functional involvement of COX-1 is indicated by the observation that central, but not systemic, pretreatment with the selective COX-1 inhibitor SC-560 attenuated the early phase of LPS-induced increases in adrenocorticotropin and corticosterone secretion. These findings support an involvement of COX-1 in bidirectional interplay between ECs and PVCs in initiating vascular PGE(2) and downstream HPA response to proinflammatory challenges.
García-Bueno
Borja
B
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and Clayton Medical Research Foundation, La Jolla, California 92037, USA.
Serrats
Jordi
J
Sawchenko
Paul E
PE
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D007124:Immunoenzyme Techniques / Q000379:methods; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007276:Injections, Intraventricular / Q000379:methods; D053583:Interleukin-1beta / Q000008:administration & dosage; D008070:Lipopolysaccharides; D008081:Liposomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014841:von Willebrand Factor / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008081:Liposomes; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D014841:von Willebrand Factor; D000324:Adrenocorticotropic Hormone; D051545:Cyclooxygenase 1; D015232:Dinoprostone; D003345:Corticosterone