Estrogen inhibits LPS-induced IL-6 production in macrophages partially via the nongenomic pathway

17 beta-estradiol (E-2)-signaling is widely considered to be mediated through the transcription- regulating intracellular estrogen receptor (iER). In this study, using the cellimpermeable E-2-BSA, we investigated the nongenomic effects of E-2 on the IL-6 production, MAPK and transcription factor activation following LPS stimulation in mouse bone marrow-derived macrophages (BMMs). It was found that E-2 normalized LPS-induced IL-6 production in BMMs. Although the increase in IL-6 production induced by LPS was also attenuated by E-2-BSA treatment, the capacity of BMMs to produce the IL-6 cytokine remained higher than the control. In addition, the iER blocker, ICI 182780, did not abolish the total effects of E-2 on LPS-stimulated IL-6 production capacity in BMMs. Furthermore, E-2 and E-2-BSA attenuated the LPS activation of p38 but not that of ERK1/2 and JNK. The p38 inhibitor, SB 203580, significantly reduced the LPS-induced IL-6 production. Moreover, E-2 and E-2-BSA inhibited LPS-induced activation of NF-kappa B. This inhibitory effect was associated with decreases in nuclear p65 protein levels. Taken together, these results indicate that E-2 has an inhibitory effect on LPS-induced IL-6 production in BMMs through inhibition of p38 MAPK phosphorylation, and blockade of NF-kappa B activation. These effects are mediated at least in part via a nongenomic pathway.