The anti-inflammatory effects of selenium are mediated through 15-deoxy-Delta12,14-prostaglandin J2 in macrophages

• Published in: The Journal of biological chemistry 2007-06, Vol.282 (25), p.17964
• Main Authors: Vunta, Hema, Davis, Faith, Palempalli, Umamaheswari D, Bhat, Deepa, Arner, Ryan J, Thompson, Jerry T, Peterson, Devin G, Reddy, C Channa, Prabhu, K Sandeep
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Arachidonic Acid - chemistry; Cell Line; Cysteine - chemistry; Gene Expression Regulation - drug effects; Lipopolysaccharides - metabolism; Macrophages - metabolism; Mass Spectrometry; Mice; NF-kappa B - metabolism; Oxidation-Reduction; PPAR gamma - metabolism; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Selenium - chemistry; Selenium - pharmacology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M703075200

Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-kappaB-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-kappaB cascade, IkappaB-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-Delta12,14-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.