Autoimmune rheumatologic diseases
ERα plays a significant role in systemic lupus erythematosus (SLE) pathogenesis, an inflammatory disease with a profound sex bias affecting females 9:1 over males. Treatment options for SLE patients are limited and have significant side effects. The development of novel therapeutic targets is of great clinical importance. Lupus mice with a deletion of the ERα AF-1 activation domain have significantly prolonged survival and less renal disease. Ligand bound ERα impacts several immune cell types and affects transcription of inflammatory mediators. Selective estrogen receptor modulators (SERMs) were developed to selectively induce non-genomic effects of ERs in breast cancer yet retain metabolic and vascular protection without impacting fertility or reproductive tissue. Their effects in immune cells have not been investigated. The effects of SERMs on bone marrow derived dendritic cells (BMDCs) isolated from lupus-prone mice prior to disease onset were tested. mRNA concentrations of proinflammatory cytokines important in SLE pathogenesis were measured. To assess the non-genomic effects of the SERMs on ERα in immune cells, phosphorylation of ERK kinase (a MAPK pathway marker) was analyzed. Our results demonstrate that these novel SERMs reduce mRNA expression of IL6 and MCP-1 in TLR-stimulated BMDCs after 24 hours, but not as potently as estrogen. Future results from this study will determine the potential role of SERMs in modulating the effects of ERα in immune cells, characterize the non-genomic effects of ERα in immune cells and lay the foundation for the potential use of these compounds in the treatment SLE and other immune mediated diseases.