The induction of the lupus phenotype by estrogen is via an estrogen receptor-α-dependent pathway

In order to investigate the roles of ER subtypes in the estrogen-induced lupus phenotype, ERα-deficient (ERα−/−) and wild-type mice (WT) were injected monthly with estradiol (E-2) starting at 8 weeks. In WT mice, E-2 treatment induced a lupus phenotype, with accelerated death and increased kidney damage, as well as Th2-type serum cytokine and autoantibody production. In contrast, only minimal changes were observed in ERα−/− mice after E-2 treatment. In a separate study, we found that in immune cells of autoimmune-prone SNF1 and non-autoimmune DBF1 mice, both ERα and ERβ were differentially expressed and modulated by E-2. In SNF1 mice, there were more CD4+ and CD8+ T cells constitutively expressing ERα, and the percentages of ERα+ dendritic cells and macrophages were increased after E-2 exposure compared to DBF1 mice. Taken together, these observations strongly suggest a role for ERα in E-2-induced development of the lupus phenotype.