Estrogen suppresses IL-1β-mediated induction of COX-2 pathway in rat cerebral blood vessels

Abstract

Ospina, Jose A., Holly N. Brevig, Diana N. Krause, and Sue P. Duckles. Estrogen suppresses IL-1␤-mediated induction of COX-2 pathway in rat cerebral blood vessels. Am J Physiol Heart Circ Physiol 286: H2010-H2019, 2004. First published December 18, 2003 10.1152/ajpheart.00481.2003.-Interleukin (IL)-1␤ 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-1␤ 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-1␤ injections (10 g/kg ip), and then cerebral vessels were isolated for biochemical and contractile measurements. In estrogen-deficient rats, IL-1␤ 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-1␤ 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 mol/l). In contrast, in animals treated with estrogen, IL-1␤ had no significant effect on COX-2 protein levels, PGE2 production, or vascular tone. Combined treatment with 17␤-estradiol and medroxyprogesterone acetate also prevented increases in PGE2 production after IL-1␤ treatment, but treatment with 17␣-estradiol had no effect. IL-1␤ induction of COX-2 protein was prevented by treatment with the nuclear factor-B inhibitor caffeic acid phenethyl ester (20 mg/kg ip), and estrogen treatment reduced cerebrovascular nuclear factor-B activity. Estrogen thus has potent anti-inflammatory effects with respect to cerebral vascular responses to IL-1␤. These effects may have important implications for the incidence and severity of cerebrovascular disease.17␤-estradiol; cyclooxygenase-2; prostaglandin E 2; nuclear factor-B; interleukin-1␤

Estradiol Is Required for a Proper Immune Response to Bacterial and Viral Pathogens in the Female Brain

“…Inducible NO synthase expression is attenuated by E 2 , though the latter failed to alter NF-B activation in primary rat microglia and N9 microglial cell lines (15). Ospina et al (39) have reported that estrogen decreases the inflammatory response to IL-1 in the brain in OVX animals and that sex hormone replacement in OVX rats attenuated LPS fever (40), but it potentiated IL-1␤-induced fever and cyclooxygenase-2 expression in the brain (41). E 2 was also found to significantly prevent LPS-induced microglial reactivity in an ER␣-dependent manner (13,14).…”

Vascular Actions of Estrogens: Functional Implications

“…Estrogenic abrogation of inflammation initiated by TNF-␣ is perhaps the most consistent of these effects and may be critical for linking infection to cardiovascular disease as TNF-␣ increases transiently even with low levels of lipopolysaccharide challenge (Jayachandran et al, 2007). Interestingly, in rats estrogen has been shown to suppress vascular inflammatory responses to IL-1␤ and lipopolysaccharide treatments, and this response has also been shown to vary through the estrous cycle (Galea et al, 2002;Ospina et al, 2004;Sunday et al, 2006). An intriguing result is that this anti-inflammatory effect of estrogen is lost in older female animals (Miller et al, 2004a;Sunday et al, 2007).…”

T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFκB-dependent Repression of the COX-2 Promoter

“…Known inhibitors of COX-2 include estrogens, antioxidants, and p53 (31)(32)(33). The presence of active p53 in particular has been shown to decrease both the mRNA and protein levels of Cox-2 in mouse embryo fibroblasts (33).…”