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, ER alpha-deficient (ER alpha(-/-)) 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 ER alpha(-/-) 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 ER alpha and ER beta were differentially expressed and modulated by E-2. In SNF1 mice, there were more CD4(+) and CD8(+) T cells constitutively expressing ER alpha, and the percentages of ER alpha+ dendritic cells and macrophages were increased after E-2 exposure compared to DBF1 mice. Taken together, these observations strongly suggest a role for ER alpha in E-2-induced development of the lupus phenotype. (C) 2009 Elsevier Inc. All rights reserved.