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INFLAMMATION AND IMMUNOPHARMACOLOGY

Ethyl Pyruvate Inhibits Nuclear Factor-B-Dependent Signaling by Directly Targeting p65

Departments of Critical Care Medicine (Y.H., J.A.E., R.Y., R.L.D., M.P.F.), Pathology (R.L.D.), and Surgery (M.P.F.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Ethyl pyruvate has been shown to have anti-inflammatory properties in numerous cell culture and animal studies. In this series of experiments, we tested the hypothesis that ethyl pyruvate inhibits signaling by the pro-inflammatory transcription factor, NF-B. Ethyl pyruvate inhibited luciferase expression in lipopolysaccharide-stimulated murine macrophage-like RAW 264.7 cells transfected with an NF-B-dependent luciferase reporter vector. Ethyl pyruvate also decreased NF-B DNA-binding activity in lipopolysaccharide-stimulated RAW 264.7 cells and decreased lipopolysaccharide-induced expression of an NF-B-dependent gene, inducible nitric oxide synthase. Ethyl pyruvate had no effect on the degradation of IB or IB in lipopolysaccharide-stimulated RAW 264.7 cells, suggesting that ethyl pyruvate acts distally to this step in the activation of NF-B. In a cell-free system, binding of p50 homodimers to an NF-B consensus oligonucleotide sequence was unaffected by ethyl pyruvate over a wide range of concentrations, indicating that ethyl pyruvate probably does not modify or interact with the p50 subunit of NF-B. In contrast, ethyl pyruvate inhibited DNA binding by ectopically overexpressed wild-type p65 homodimers. However, ethyl pyruvate failed to inhibit the DNA-binding activity of homodimers of an overexpressed mutant form of a p65 with substitution of serine for cysteine 38. Taken together, these results suggest that ethyl pyruvate inhibits DNA-binding by covalently modifying p65 at Cys³⁸. We conclude that some of the beneficial anti-inflammatory effects of ethyl pyruvate may be due to modification of p65, thereby inhibiting signaling via the NF-B pathway.

Address correspondence to: Dr. Mitchell P. Fink, Department of Critical Care Medicine, 615 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: finkmp{at}ccm.upmc.edu

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