Selenium (Se) is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-kB-dependent proinflammatory gene expression. To understand the molecular mechanisms underlying the antiinflammatory property of Se, we examined the activity of a key kinase of the NF-kB cascade, IkB-kinase b (IKKb) subunit, as a function of cellular Se status in murine primary bone marrow-derived macrophages (BMDM) and RAW264.7 macrophage-like cell line. In vitro kinase assays revealed that lipopolysaccharide (LPS)-treatment decreased the activity of IKKb in Se-supplemented BMDM and RAW264.7 macrophages. Stimulation by LPS of Se-supplemented macrophages resulted in a time-dependent increase in 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) formation, an endogenous inhibitor of IKKb activity. Further analysis revealed that inhibition of IKKb activity in Se-supplemented cells correlated with the Michael addition product of IKKb with 15d-PGJ2; while such an adduct formation was not seen in the Se-deficient macrophages. In addition, antiinflammatory activities of Se were also mediated by the 15d-PGJ2-dependent activation of the peroxisome proliferator activated nuclear receptor-g in macrophages. Experiments using specific COX inhibitors and genetic knockdown approaches indicated that the COX-1, and not the COX-2 pathway, was responsible for the increased synthesis of 15d-PGJ2 in Se-supplemented macrophages. Taken together, our results suggest that Se-supplementation increases the production of 15d-PGJ2 as an adaptive response to protect cells against oxidative stress-induced proinflammatory gene expression. More specifically, thiol group modification of IKKß catalytic subunit by 15d-PGJ2 represents a previously undescribed mechanism of action of Se, which extends the code for redox regulation of proinflammatory gene expression.