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

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 proinflammatory cytokines such as IL-1, implicated in the pathogenesis of the disease. In this study we examined whether 17beta-estradiol (E2) induced IL-1alpha 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-1alpha mRNA expression in both cell types in an estrogen receptor-dependent manner. In MH7A cells ERalpha but not ERbeta mediated the effects of E2. Deletion and mutation analysis revealed that a GC-rich region within the IL-1alpha 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 ERalpha interacted physically regardless of the presence of E2. Physical interaction was also observed between ERalpha and histone deacetylase 2 (HDAC2), and E2 induced the dissociation of HDAC2 from ERalpha. These results suggest that E2 induces the dissociation of corepressor HDAC2 from ERalpha, which leads to the augmentation of Sp1 transcriptional activity through the GC-rich region within the IL-1alpha gene promoter.