17.BETA.-Estradiol Primes Elicitation of Inducible Nitric Oxide Synthase Expression by Lipopolysaccharide and Interferon-.GAMMA. in Mouse Macrophage Cell Line J774.1

Abstract

The effects of estrogenic compounds on nitric oxide (NO) production by macrophages were examined. 17β-Estradiol promoted NO production triggered by lipopolysaccharide (LPS) and/or interferon (IFN)-γ in the mouse macrophage cell line J774.1. Other estrogen-like substances such as estrone, 17α-ethynylestradiol and bisphenol A also enhanced NO synthesis, but this NO synthesis was not activated by Ca 2+ ionophore A23187. RT-PCR analysis demonstrated induction of inducible nitric oxide synthase (iNOS) mRNA in J774.1 cells exposed to 17β-estradiol. Although the estrogen receptor (ER)-antagonist ICI-182780 partially suppressed the promoting effect of 17β-estradiol on NOS activity, there was little ERα detectable by RT-PCR from J774.1 cells. These results suggest that ERs may participate only partially in iNOS mRNA transcription in J774.1 cells and that 17β-estradiol may act directly through other unknown intracellular signal transduction(s) that are activated by LPS and IFN-γ.

17β-Estradiol enhances expression of inflammatory cytokines and inducible nitric oxide synthase in mouse contact hypersensitivity

“…E2 enhanced auricle edema at 6 h after elicitation, and showed a tendency to enhance edema at 24 h when compared to vehicle-treated mice. The increase in IFN-γ expression at 6 h coincided with the increase in auricle swelling at 6 h. E2 failed to promote swelling at 24 h, enhanced IL-10 expression at 24 h, and suppressed the IFN-γ effect at 48 h. We have reported that E2 enhances iNOS expression in the mouse macrophage J774.1 cell line [14]. In the present study, it was expected that macrophage activity would be augmented directly by E2, or indirectly via the E2-induced increase in IFN-γ.…”

“…Vascular dilation is also induced by inflammatory cytokines such as IFN-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β [12,13]. We have previously reported that E2 enhanced inducible nitric oxide synthase (iNOS) in the mouse macrophage cell line J774.1, and that E2 enhanced IFN-γ in mouse CHS [9,14]. These data suggest that E2, both directly and indirectly, enhances iNOS expression to dilate vascular vessels.…”

In Vitro and In Vivo Evidence for Anti-Inflammatory Properties of 2-Methoxyestradiol

“…Numerous studies have examined the actions of 17␤-estradiol on macrophages. Such studies confirm a mechanistic role for high-affinity estrogen receptors, but yield conflicting reports as to the effects of 17␤-estradiol on cell function, ranging from inhibition to promotion of activation (compare, for example, findings reported by Hayashi et al, 1998;Lu et al, 2004;Vegeto et al, 2004;Sakazaki et al, 2005). On the other hand, little attention has been given to the effects of 17␤-estradiol metabolites, such as 2MEO, on macrophage function.…”

“…Estrogen receptor-␤ agonists have attracted attention as potential anti-inflammatory agents (Koehler et al, 2005). Previous studies in LPS/IFN␥-stimulated J774 cells found in one case modest suppression of nitric-oxide production by 17␤-estradiol (Hayashi et al, 1998) and in another case enhancement (Sakazaki et al, 2005), but did not examine other inflammatory mediators. However, in the present study concentrations of 17␤-estradiol far greater than those required to saturate high-affinity estrogen receptors had no effect on J774 macrophage activation.…”