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B Kinase-
regulates LPS-induced TNF
production in cardiac myocytes through NF-B p65 subunit phosphorylation
1 Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
2 Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
3 Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA; Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: trogers{at}som.umaryland.edu.
Tumor Necrosis Factor-
(TNF-) is now recognized as a significant contributor to myocardial dysfunction. While several studies suggest that members of the Nuclear Factor-
B (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 the post-translational modification of NF-B subunits suggest that the current 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 lipopolysaccharide (LPS)-induced TNF- production is accompanied by a 12-fold increase in phosphorylation of p65 at serine 536, a modification associated with the enhancement of p65 transactivation potential. Pharmacologic inhibition of the Inhibitor-B Kinase-
(IKK) reduced LPS-induced TNF- production by 38-fold, TNF- mRNA levels by 6-fold, IB- phosphorylation by 5-fold, IB- degradation by 2-fold and p65 phosphorylation by 6-fold. Similarly, overexpression of a dominant negative p65 reduced TNF- production 3.5-fold while overexpression of dominant negative IKK (dnIKK) reduced LPS-induced TNF- production 2-fold and p65 phosphorylation 2-fold. Interestingly, overexpression of dominant negative IKK (dnIKK) had no effect on p65 phosphorylation or TNF- production revealing that IKK, not IKK, plays a central role in the regulation of p65 phosphorylation at serine 536 and TNF- production in heart. Finally, we demonstrated, using a chromatin immunoprecipiation assay, that LPS stimulates the recruitment of serine-536-phosphorylated p65 to the TNF- gene promoter in cardiac myocytes. Taken together, these data provide compelling evidence of 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.
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