TLR2 agonists are well known for inducing NF-kB activation and inflammation, while estrogen receptor-alpha (ER-α) is a regulator of estrogen-mediated anti-inflammatory responses. In the present work, we determined the role of ER-α and phosphorylated ER-α in TLR2 agonist-induced MCP1 production in mesangial cells. We found that TLR2 agonists induced nuclear localization of phospho-ER-α (serine 118), and estrogen and TLR2 agonists both induced phosphorylation of ER-α at the serine 118 and 104/106 positions. Incubation of MRL/lpr mesangial cells with estrogen was found to attenuate TLR2 agonist-mediated MCP1 production. To determine the mode of action of ER-α/pER-α (serine-118), we used the ER-α inhibitor MPP and transfected mesangial cells with ER-α siRNA. ER-α inhibition was found to decrease MCP1 production in mesangial cells. Thus, ER-α/pER-α is an intermediate regulator for both TLR2-mediated MCP1 production during inflammation and estrogen-mediated anti-inflammatory signals in mesangial cells.