Steroid hormones exert genotropic effects through members of the nuclear hormone 
receptor family. In the present study, we examined the effects of 17β-estradiol 
(E2) on nitric oxide (NO) production following lipopolysaccharide (LPS) 
stimulation and investigated the mechanisms in mouse bone marrow-derived 
macrophages (BMMs). E2 alone did not affect NO production. In contrast, E2 
inhibited LPS-induced production of NO in BMMs. Using a cell-impermeable E2 
conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic 
effects of estrogen, we found that the increase in NO production induced by LPS 
was also attenuated. In addition, the intracellular estrogen receptor blocker, 
ICI 182780, only partially antagonized the total effects of E2 on LPS-stimulated 
NO production capacity. E2 also attenuated the LPS activation of p38 
mitogen-activated protein kinase (MAPK) but not that of extracellular-regulated 
protein kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). This 
attenuation was not abrogated by ICI 182780. Moreover, the p38 inhibitor, SB 
203580, greatly reduced the LPS-induced NO production, and the remaining NO 
levels were no longer regulated by E2. Additionally, E2-BSA inhibited 
LPS-mediated changes in p38 MAPK activation to the same extent as E2. Moreover, 
E2 and E2-BSA inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) 
and activator protein 1 (AP-1). This inhibitory effect of E2 was only partially 
antagonized by ICI 182780. Taken together, these results suggest that E2 has an 
inhibitory effect on LPS-induced NO production in BMMs through inhibition of p38 
MAPK phosphorylation, and blockade of NF-κB and AP-1 activation. These effects 
are mediated at least in part via a nongenomic pathway.