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

In order to investigate the roles of ER subtypes in the estrogen-induced lupus phenotype, ERalpha-deficient (ERalpha(-/-)) 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 ERalpha(-/-) mice after E-2 treatment. In a separate study, we found that in immune cells of autoimmune-prone SNF(1) and non-autoimmune DBF(1) mice, both ERalpha and ERbeta were differentially expressed and modulated by E-2. In SNF(1) mice, there were more CD4(+) and CD8(+) T cells constitutively expressing ERalpha, and the percentages of ERalpha+ dendritic cells and macrophages were increased after E-2 exposure compared to DBF(1) mice. Taken together, these observations strongly suggest a role for ERalpha in E-2-induced development of the lupus phenotype.