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Originally published In Press as doi:10.1074/jbc.M703075200 on April 17, 2007

J. Biol. Chem., Vol. 282, Issue 25, 17964-17973, June 22, 2007
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The Anti-inflammatory Effects of Selenium Are Mediated through 15-Deoxy-{Delta}12,14-prostaglandin J2 in Macrophages*

Hema Vunta{ddagger}, Faith Davis{ddagger}, Umamaheswari D. Palempalli{ddagger}, Deepa Bhat{ddagger}, Ryan J. Arner{ddagger}, Jerry T. Thompson{ddagger}, Devin G. Peterson§, C. Channa Reddy{ddagger}1, and K. Sandeep Prabhu{ddagger}2

From the {ddagger}Department of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, §Department of Food Science, Pennsylvania State University, University Park, Pennsylvania 16802

Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-{kappa}B-dependent pro-inflammatory gene expression. To understand the molecular mechanisms underlying the anti-inflammatory property of selenium, we examined the activity of a key kinase of the NF-{kappa}B cascade, I{kappa}B-kinase beta (IKKbeta) subunit, as a function of cellular selenium status in murine primary bone marrow-derived macrophages and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that selenium supplementation decreased the activity of IKKbeta in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of selenium-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKbeta activity. Further analysis revealed that inhibition of IKKbeta activity in selenium-supplemented cells correlated with the Michael addition product of 15d-PGJ2 with Cys-179 of IKKbeta, while the formation of such an adduct was significantly decreased in the selenium-deficient macrophages. In addition, anti-inflammatory activities of selenium were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator-activated nuclear receptor-{gamma} in macrophages. Experiments using specific cyclooxygenase (COX) inhibitors and genetic knockdown approaches indicated that COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d-PGJ2 represents a previously undescribed code for redox regulation of gene expression by selenium.


Received for publication, April 11, 2007

* Some of these results were presented at the 8th International Symposium on Selenium in Biology and Medicine in Madison, WI, and the 9th International Symposium on Eicosanoids and other Bioactive Lipids in Cancer, Inflammation, and Related Diseases in San Francisco, CA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence may be addressed: Dept. of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, 115 William L. Henning Building, Pennsylvania State University, University Park, PA 16802. Tel.: 814-865-7696; Fax: 814-863-6140; E-mail: ccr1{at}psu.edu. 2 To whom correspondence may be addressed: Dept. of Veterinary and Biomedical Sciences, Centers for Molecular Toxicology and Carcinogenesis, and Molecular Immunology and Infectious Disease, 115 William L. Henning Building, Pennsylvania State University, University Park, PA 16802. Tel.: 814-863-8976; Fax: 814-863-6140; E-mail: ksp4{at}psu.edu.


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