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15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) mediates repression of TNF-alpha by decreasing levels of acetylated histone H3 and H4 at its promoter.
Engdahl, Ryan; Monroy, M Alexandra; Daly, John M.
Afiliação
  • Engdahl R; Temple University School of Medicine, Department of Surgery, 3400 North Broad Street, Philadelphia, PA 19140, USA. rengdahl@temple.edu
Biochem Biophys Res Commun ; 359(1): 88-93, 2007 Jul 20.
Article em En | MEDLINE | ID: mdl-17532302
Prostaglandin metabolite 15-Deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) is known to inhibit a number of pro-inflammatory cytokines as well as being a ligand for nuclear receptor PPARgamma. We investigated the ability of 15d-PGJ2 to inhibit TNF-alpha gene expression through mechanisms that involve histone modification. Pretreatment with 15d-PGJ2 (10 microM) inhibited LPS-stimulated TNF-alpha mRNA in THP-1 monocytes or PMA-differentiated cells to nearly basal levels. A specific PPARgamma ligand, GW1929, failed to inhibit LPS-induced TNF-alpha mRNA expression nor did a PPARgamma antagonist, GW9662, alter the repression of TNF-alpha mRNA in LPS-stimulated cells pretreated with 15d-PGJ2 suggesting a PPARgamma-independent inhibition of TNF-alpha mRNA in THP-1 cells. Transfection studies with a reporter construct and subsequent treatment with 15d-PGJ2 demonstrated a dose-dependent inhibition of the TNF-alpha promoter. Additional studies demonstrated that inhibition of histone deacetylases with trichostatin A (TSA) or overexpression of histone acetyltransferase CBP could overcome 15d-PGJ2-mediated repression of the TNF-alpha promoter, suggesting that an important mechanism whereby 15d-PGJ2 suppresses a cytokine is through factors that regulate histone modifications. To examine the endogenous TNF-alpha promoter, chromatin immunoprecipitations (ChIP) were performed. ChIP assays demonstrated that LPS stimulation induced an increase in histone H3 and H4 acetylation at the TNF-alpha promoter, which was reduced in cells pretreated with 15d-PGJ2. These results highlight the ability of acetylation and deacetylation factors to affect the TNF-alpha promoter and demonstrate that an additional important mechanism whereby 15d-PGJ2 mediates TNF-alpha transcriptional repression by altering levels of acetylated histone H3 and H4 at its promoter.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Histonas / Monócitos / Prostaglandina D2 / Ativação Transcricional / Regiões Promotoras Genéticas / Fator de Necrose Tumoral alfa Limite: Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Histonas / Monócitos / Prostaglandina D2 / Ativação Transcricional / Regiões Promotoras Genéticas / Fator de Necrose Tumoral alfa Limite: Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article