ABSTRACT
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.
Subject(s)
Estradiol/metabolism , Estrogen Receptor alpha/metabolism , Estrogens/metabolism , Lupus Erythematosus, Systemic/metabolism , Animals , Autoantibodies/blood , Autoantibodies/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Separation , Cytokines/biosynthesis , Cytokines/immunology , Enzyme-Linked Immunosorbent Assay , Estradiol/pharmacology , Estrogens/pharmacology , Flow Cytometry , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/pathology , Lupus Nephritis/immunology , Lupus Nephritis/pathology , Mice , Mice, Knockout , PhenotypeABSTRACT
The Bcl-2 family, including antiapoptotic and proapoptotic members, plays key regulating roles in programmed cell death. We report the characterization of a new member of the bcl-2 family, encoded by herpesvirus of turkeys (HVT). The product of this gene shares 80% homology with Nr-13, an apoptosis inhibitor, which is overexpressed in avian cells transformed by the v-src oncogene. This new gene, that we propose to call vnr-13, is the first member of the bcl-2 family to be isolated among alpha-herpesviruses. Results from cells expressing the HVT-vnr-13 gene product show that the encoded protein inhibits apoptosis and also reduces the rate of cellular proliferation. Contrary to all bcl-2 homologues found in gamma-herpesvirus, which are intronless, vnr-13 has the same organization as the cellular nr-13 gene. Hence, the HVT vnr-13 gene may have been acquired from a reverse transcriptase product of an unspliced precursor RNA, or via direct recombination with the host chromosomal DNA.
