title: Repression of TNF-alpha-induced E-selectin expression by PPAR activators: involvement of transcriptional repressor LRF-1/ATF3.
abstract: Peroxisome proliferator-activated receptor (PPAR) activators were shown to inhibit the expression of E-selectin of human vascular endothelial cells in response to tumor necrosis factor-alpha (TNF-alpha). Troglitazone, pioglitazone, alpha-clofibrate, and 15-deoxy-Delta12,14-prostaglandin J2 all inhibited the TNF-alpha-stimulated E-selectin gene transcription in reporter assay. To further clarify the underlying transcriptional regulation, nuclear factor(s) that binds to the nuclear factor-endothelial leukocyte adhesion molecule 1 (NF-ELAM1) site of the E-selectin gene promoter was investigated. The activators caused a significant induction of liver regenerating factor 1 (LRF1)/activating transcription factor 3 (ATF3), which bound to the NF-ELAM1 site and repressed the TNF-alpha-induced E-selectin gene expression. From these data, the effect of PPAR activators was mediated, in part, through the induction of LRF1/ATF3. This might provide a novel molecular mechanism of anti-inflammatory effect of PPAR activators.
authors.affiliation: Department of Biochemical Genetics, Faculty of Medicine, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nawa
authors.forename: M T
authors.initials: MT
authors.lastname: Nawa
authors.forename: Y
authors.initials: Y
authors.lastname: Cai
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: I
authors.initials: I
authors.lastname: Uchimura
authors.forename: S
authors.initials: S
authors.lastname: Narumi
authors.forename: F
authors.initials: F
authors.lastname: Numano
authors.forename: S
authors.initials: S
authors.lastname: Kitajima
mesh_terms: D051700:Activating Transcription Factor 3; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D019040:E-Selectin / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D019040:E-Selectin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C068616:liver regeneration factor 1