title: 17Beta-estradiol inhibits MCP-1 production in human keratinocytes.
abstract: A chemokine, monocyte chemoattractant protein 1 (MCP-1), attracts macrophages. The production of MCP-1 is enhanced in keratinocytes of psoriatic lesions, which may contribute to macrophage infiltration into the lesions. It is known that estrogen regulates the course of psoriasis. We examined in vitro effects of 17beta-estradiol (E2) on MCP-1 production by human keratinocytes. E2 inhibited constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced MCP-1 secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of E2 were counteracted by estrogen receptor antagonist ICI 182 780. GC-rich Sp1 element and activator protein 1 (AP-1) element on MCP-1 promoter were required for constitutive and 12-O-tetradecanoylphorbol-13-acetate-induced transcription, respectively, and involved in transrepression by E2. E2 inhibited constitutive Sp1 and 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 transcriptional activities whereas it did not inhibit DNA binding of Sp1 or AP-1 c-Fos/c-Jun. E2 inhibited Sp1 and AP-1 transcriptional activities and MCP-1 promoter activity in estrogen receptor beta (ERbeta) transfected SKBR3 cells. Deletion of the A/B region or mutation of activation function 2 in ERbeta abrogated E2-dependent transcriptional inhibition by ERbeta whereas mutation of DNA-binding domain retained the inhibitory effects. Transfection of ERbeta enhanced the inhibitory effects of E2 on Sp1 and AP-1 transcriptional activities and MCP-1 promoter activities in nontransfected keratinocytes. Coimmunoprecipitation studies showed an E2-dependent association of ERbeta with Sp1 or AP-1 in ERbeta-transfected keratinocytes. These results suggest that E2-bound ERbeta may inhibit MCP-1 gene expression by inhibiting Sp1 and AP-1 transcriptional activities in keratinocytes. A/B region and intact activation function 2 of ERbeta may be responsible for the effects of E2.
authors.affiliation: Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D016329:Sp1 Transcription Factor / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D004958:Estradiol; D013755:Tetradecanoylphorbol Acetate