Estrogen and the environmental estrogen bisphenol A differentially regulate cathepsin activity in a mouse model for Systemic Lupus Erythematosus

Abstract

The autoimmune disease Systemic Lupus Erythematosus (SLE) is linked to estrogen (E2) and may be affected by the environmental estrogen bisphenol A (BPA) that is used in plastics production. E2 and BPA bind to estrogen receptors (ER), altering cellular pathways. We investigated the effect of E2 and BPA on the regulation of cathepsins, central enzymes in major histocompatibility class II (MHC‐II) antigen presentation. A bioinformatic analysis showed that many cathepsins have putative estrogen response elements (ERE) making them candidates for regulation by compounds that activate ER. Splenocytes isolated from C57/Bl6 and lupus‐prone NZB/WF1 female mice were treated with varying concentrations of hormone. B cells were also purified using magnetic activated cell sorting and populations were routinely enriched to >90% as verified by fluorescence activated cell scanning. Following treatment, cathepsin expression (via Western blotting) and activity (by fluorescence enzyme activity assays) were monitored. In both cell populations we found that cathepsins B and L were increased in NZB/WF1 but not control mice when exposed to E2, while the opposite effect was seen with BPA. These results indicate that MHC‐II antigen processing and presentation is differentially regulated in SLE animals and that environmental estrogens can affect immune function. Funded by NIH grant 1R15ES013947‐01, Merck/AAAS USRP, and Van Sant.