title: Inhibition of phorbol ester-dependent peroxiredoxin I gene activation by lipopolysaccharide via phosphorylation of RelA/p65 at serine 276 in monocytes.
abstract: Peroxiredoxin I (Prx I) is an antioxidant enzyme with thioredoxin-dependent peroxidase activity which is involved in various cellular processes such as regulation of cell proliferation. Here, it is shown that the proinflammatory mediator lipopolysaccharide (LPS) inhibits the induction of Prx I expression and promoter activity by the phorbol ester 12-O-tetradecanoylphorbol- 13-acetate (TPA) in RAW264.7 monocytes, but not that of cyclooxygenase-2. LPS-dependent repression of Prx I induction by TPA was mediated via a newly identified kappaB site in the Prx I promoter, but the "classical" NF-kappaB cascade was not involved in this regulatory pathway, because IkappaB did not affect LPS-mediated Prx I repression. By contrast, phosphorylation of p65 at serine 276, which enhances the transcriptional activity of NF-kappaB, was up-regulated by TPA and was reduced by simultaneous exposure to LPS. Functional studies with Gal4-p65 constructs revealed that serine 276 is crucial to confer LPS-dependent repression of TPA-mediated induction of p65 transactivation. Finally, repression of TPA-dependent Prx I induction by LPS was mediated via Bruton's tyrosine kinase as indicated by studies with the pharmacological inhibitor LFM-A13. In summary, LPS-dependent inhibition of Prx I gene activation by TPA in monocytes is regulated via a pathway that involves phosphorylation of the NF-kappaB subunit p65 at serine 276.
authors: Institut für Klinische Immunologie und Transfusionsmedizin, Justus-Liebig-Universität Giessen, D-35392 Giessen, Germany.
authors: Nastiti
authors: N
authors: Wijayanti
authors: Srivatsava
authors: S
authors: Naidu
authors: Thomas
authors: T
authors: Kietzmann
authors: Stephan
authors: S
authors: Immenschuh
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D051550:I-kappa B Kinase / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D054464:Peroxiredoxins / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D012694:Serine; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D050880:p300-CBP Transcription Factors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D051550:I-kappa B Kinase; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate