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This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/H2103    most recent 00393.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Hall, G. Articles by Rogers, T. B. Search for Related Content PubMed PubMed Citation Articles by Hall, G. Articles by Rogers, T. B.

Inhibitor-B kinase- regulates LPS-induced TNF- production in cardiac myocytes through modulation of NF-B p65 subunit phosphorylation

Departments of ¹Biochemistry and Molecular Biology and ²Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Submitted 21 April 2005 ; accepted in final form 17 June 2005

TNF- is recognized as a significant contributor to myocardial dysfunction. Although several studies suggest that members of the NF-B family of transcription factors are essential regulators of myocardial TNF- gene expression, recent developments in our understanding of the modulation of NF-B activity through posttranslational modification of NF-B subunits suggest that the present view of NF-B-dependent cytokine expression in heart is incomplete. Therefore, the goal of the present study was to examine the role of p65 subunit phosphorylation in the regulation of TNF- production in cultured neonatal ventricular myocytes. Bacterial LPS-induced TNF- production is accompanied by a 12-fold increase in phosphorylation of p65 at Ser⁵³⁶, a modification associated with enhancement of p65 transactivation potential. Pharmacological inhibition of IKK- reduced LPS-induced TNF- production 38-fold, TNF- mRNA levels 6-fold, and IB- phosphorylation 5-fold and degraded IB- 2-fold and p65 phosphorylation 6-fold. Overexpression of dominant-negative p65 reduced TNF- production 3.5-fold, whereas overexpression of dominant-negative IKK- reduced LPS-induced TNF- production 2-fold and p65 phosphorylation 2-fold. Overexpression of dominant-negative IKK- had no effect on p65 phosphorylation or TNF- production, revealing that IKK-, not IKK-, plays a central role in regulation of p65 phosphorylation at Ser⁵³⁶ and TNF- production in heart. Finally, we demonstrated, using a chromatin immunoprecipitation assay, that LPS stimulates recruitment of Ser⁵³⁶-phosphorylated p65 to the TNF- gene promoter in cardiac myocytes. Taken together, these data provide compelling evidence for the role of NF-B signaling in TNF- gene expression in heart and highlight the importance of this proinflammatory gene-regulatory pathway as a potential therapeutic target in the management of cytokine-induced myocardial dysfunction.

signal transuction; gene expression; heart; cytokines

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