17β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor α (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERα

Rheumatoid arthritis (RA) occurs four times more frequently in women than in men, although the mechanistic basis of the gender difference is unknown. RA is characterized by the overproliferation of synoviocytes producing prointlammatory cytokines such as IL-1. implicated in the pathogenesis of the disease. In this study we examined whether 17 beta-estradiol (E2) induced IL-1 alpha mRNA expression in the rheumatoid fibroblast-like cell line MH7A, as well as in primary synovial cells from RA patients, and investigated the underlying molecular mechanisms. E2 induced IL-1 alpha mRNA expression in both cell types in an estrogen receptor-dependent manner. In MH7A cells ER alpha but not ER beta mediated the effects of E2. Deletion and mutation analysis revealed that a GC-rich region within the IL-1 alpha gene promoter was responsible for the response to E2. EMSAs showed that Sp1 and Sp3 bound to the GC-rich region and that the transcriptional activity of Sp1 was up-regulated by the treatment with E2. Sp1 and ER alpha interacted physically regardless of the presence of E2. Physical interaction was also observed between ER alpha and histone deacetylase 2 (HDAC2), and E2 induced the dissociation of HDAC2 from ER alpha. These results suggest that E2 induces the dissociation of corepressor HDAC2 from ER alpha, which leads to the augmentation of Spl transcriptional activity through the GC-rich region within the IL-1 alpha gene promoter.