Estrogen suppresses IL-1beta-mediated induction of COX-2 pathway in rat cerebral blood vessels.
Interleukin (IL)-1beta is a potent inducer of inflammatory prostaglandins, which are important mediators of vascular response to cerebral injury, whereas estrogen reduces brain injury in models of ischemic stroke. Thus we examined the effects of in vivo IL-1beta exposure on cerebrovascular cyclooxygenase (COX)-2 expression and function in an animal model of chronic estrogen replacement. Estrogen-treated and nontreated ovariectomized female rats received IL-1beta injections (10 microg/kg i.p.), and then cerebral vessels were isolated for biochemical and contractile measurements. In estrogen-deficient rats, IL-1beta induced cerebrovascular COX-2 protein expression; a peak response occurred 3 h after injection. COX-2 was localized to arterial endothelium using confocal microscopy. IL-1beta increased PGE2 but not PGI2 production and decreased vascular tone as measured in isolated cerebral arteries; the latter effect was partially reversed by treatment with the selective COX-2 inhibitor NS-398 (10 micromol/l). In contrast, in animals treated with estrogen, IL-1beta had no significant effect on COX-2 protein levels, PGE2 production, or vascular tone. Combined treatment with 17beta-estradiol and medroxyprogesterone acetate also prevented increases in PGE2 production after IL-1beta treatment, but treatment with 17alpha-estradiol had no effect. IL-1beta induction of COX-2 protein was prevented by treatment with the nuclear factor-kappaB inhibitor caffeic acid phenethyl ester (20 mg/kg i.p.), and estrogen treatment reduced cerebrovascular nuclear factor-kappaB activity. Estrogen thus has potent anti-inflammatory effects with respect to cerebral vascular responses to IL-1beta. These effects may have important implications for the incidence and severity of cerebrovascular disease.
Ospina
Jose A
JA
Department of Pharmacology, College of Medicine, University of California, Irvine, California 92697-4625, USA.
Brevig
Holly N
HN
Krause
Diana N
DN
Duckles
Sue P
SP
D000818:Animals; D001808:Blood Vessels / Q000201:enzymology; D001921:Brain / Q000098:blood supply*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D007375:Interleukin-1 / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology; D010052:Ovariectomy; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects
D004967:Estrogens; D007375:Interleukin-1; D007527:Isoenzymes; D016328:NF-kappa B; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone