期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 25, 页码 17964-17973出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M703075200
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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 (IKK beta) 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 IKK beta 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 J(2) (15d- PGJ(2)) formation, an endogenous inhibitor of IKK beta activity. Further analysis revealed that inhibition of IKK beta activity in selenium-supplemented cells correlated with the Michael addition product of 15d- (P)GJ(2) with Cys-179 of IKK beta, 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-PGJ(2)-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 15dP-GJ(2) in selenium-supplemented macrophages. Taken together, our results suggest that selenium supplementation increases the production of 15d- PGJ(2) as an adaptive response to protect cells against oxidative stress-induced pro-inflammatory gene expression. More specifically, modification of protein thiols by 15d- PGJ(2) represents a previously undescribed code for redox regulation of gene expression by selenium.
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