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Molecular Analysis of the Inhibition of Monocyte Chemoattractant Protein-1 Gene Expression by Estrogens and Xenoestrogens in MCF-7 Cells¹

Department of Molecular Preventive Medicine (H.I., T.S., K.M.), University of Tokyo, School of Medicine, 7–3-1, Hongo, Bunkyoku, Tokyo 113-0033, Japan; and the Immunopathology Section, Laboratory of Molecular Immunoregulation (T.Y.), National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Address all correspondence and requests for reprints to: Prof. Kouji Matsushima, M.D., Ph.D., Department of Molecular Preventive Medicine, University of Tokyo, School of Medicine, 7–3-1 Hongo, Bunkyoku, Tokyo 113-0033, Japan. E-mail: koujim{at}m.u-tokyo.ac.jp

Xenoestrogens (XEs) are a diverse group of chemicals that mimic estrogenic actions and may have adverse effects on human health. The influence of these compounds on cytokine production or immune system function remains unclear. In this study we have examined the effects of 17ß-estradiol (E₂) and XEs on chemoattractant cytokine (chemokine) production and analyzed the molecular mechanism. Monocyte chemoattractant protein-1 (MCP-1), also termed monocyte chemotactic and activating factor, is a member of the chemokine family and attracts mainly blood monocytes. Human mammary tumor cell line MCF-7 cells produce a large quantity of MCP-1 in response to interleukin-1 (IL-1). Addition of E₂ to MCF-7 cells inhibited MCP-1 production in a dose-dependent manner. XEs, bisphenol A, and NP also inhibited MCP-1 production, although the potency was 3–4 orders of magnitude lower than that of E₂. E₂, bisphenol A, and NP inhibited MCP-1 messenger RNA expression in MCF-7 cells. Two closely located nuclear factor-B sites, A1 and A2, have been identified in the promoter of the human MCP-1 gene. A luciferase construct containing this enhancer region (pGLM-ENH) was activated by IL-1, and a mutation at either the A1 or A2 site resulted in a loss of IL-1 responsiveness. Treatment with E₂ or XEs decreased the IL-1-inducible pGLM-ENH luciferase activity significantly. In an electrophoretic mobility shift assay and supershift analysis, we found that treatment with E₂ or XEs diminished the IL-1-induced complex formation with both A1 and A2 probes, which was identified immunochemically to consist of nuclear factor-B, p50, and p65. The IL-1-induced p50/c-Rel complex to the A2 probe was also, to a lesser extent, decreased by E₂ or XE treatment. The effects of E₂ and XEs on the expression of MCP-1 seem to be much more dramatic than the effects of these agents on the promoters used in the luciferase assay, suggesting the involvement of an additional site(s) of the promoter region of the MCP-1 gene or posttranscriptional regulation of MCP-1 gene expression by E₂ and XEs. This work represents the first report describing possible regulation of immune system function by XEs through inhibiting chemokine production.

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