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-Estradiol Induces IL-1
Gene Expression in Rheumatoid Fibroblast-Like Synovial Cells through Estrogen Receptor (ER) and Augmentation of Transcriptional Activity of Sp1 by Dissociating Histone Deacetylase 2 from ER1
* Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan;
Central Research Laboratories, Kissei Pharmaceutical Company, Azumino, Japan;
Molecular Cellular Pathology Research Unit, Institute of Physical and Chemical Research, Wako, Japan; and
Departments of Laboratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan
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 17
-estradiol (E2) induced IL-1
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 mRNA expression in both cell types in an estrogen receptor-dependent manner. In MH7A cells ER but not ER mediated the effects of E2. Deletion and mutation analysis revealed that a GC-rich region within the IL-1 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 interacted physically regardless of the presence of E2. Physical interaction was also observed between ER and histone deacetylase 2 (HDAC2), and E2 induced the dissociation of HDAC2 from ER. These results suggest that E2 induces the dissociation of corepressor HDAC2 from ER, which leads to the augmentation of Sp1 transcriptional activity through the GC-rich region within the IL-1 gene promoter.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Grant-in Aid for Scientific Research (B) from the Japan Society for the Promotion of Science; Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology; and Grants in-Aid for Scientific Research from Nagoya City University.
2 Address correspondence and reprint requests to Dr. Kikuo Onozaki, Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Japan. E-mail address: konozaki{at}phar.nagoya-cu.ac.jp
3 Abbreviations used in this paper: RA, rheumatoid arthritis; DBD, DNA binding domain; E2, 17-estradiol; ER, estrogen receptor; ERE, estrogen response element; HDAC, histone deacetylase; IL-1Ra, IL-1R agonist; LBD, ligand binding domain.
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