A Gender-Dependent Molecular Switch of Inflammation via MyD88/Estrogen Receptor-alpha Interaction

Most Toll-like receptors and IL-1/IL-18 receptors activate a signaling cascade via the adaptor molecule MyD88, resulting in NF-{kappa}B activation and inflammatory cytokine and chemokine production. Females are less susceptible than males to inflammatory conditions, presumably due to protection by estrogen. Here we show that MyD88 interacts with a methylated, cytoplasmic form of estrogen receptor-alpha (methER-). This interaction is required for NF-{kappa}B transcriptional activity and pro-inflammatory cytokine production, and is dissociated by estrogen. Importantly, we show a strong gender segregation in gametogenic reproductive organs, with MyD88/methER- interactions found in testicular tissues and in ovarian tissues from menopausal women, but not in ovaries from women age 49 and less -suggesting a role for estrogen in disrupting this complex in situ. Collectively, our results indicate that the formation of MyD88/methER- complexes during inflammatory signaling and their disruption by estrogen may represent a mechanism that contributes to gender bias in inflammatory responses.