Abstract
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.
Highlights
Macrophages play central roles as effector cells in inflammatory reactions and cell-mediated immune responses
The selenium-supplemented and selenium-deficient bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages were used in all the experiments described below
Supplementation with selenium has been positively correlated with lowered incidences in prostate cancer and HIV replication, where macrophage activation is a crucial step in the inflammatory processes that form the underlying basis of disease progression [38]
Summary
Macrophages play central roles as effector cells in inflammatory reactions and cell-mediated immune responses While performing these functions, these cells produce such reactive oxygen species in the form of superoxide anion, hydrogen peroxide, hydroxyl, and lipid peroxyl radicals along with a great number of pro-inflammatory substances, including complement components, PGs, chemokines, and cytokines like interleukin-1 and tumor necrosis factor-␣ [1]. These cells produce such reactive oxygen species in the form of superoxide anion, hydrogen peroxide, hydroxyl, and lipid peroxyl radicals along with a great number of pro-inflammatory substances, including complement components, PGs, chemokines, and cytokines like interleukin-1 and tumor necrosis factor-␣ [1] Such reactions represent a potentially toxic insult, which if not counteracted, will lead to membrane dysfunction, DNA damage and inactivation of proteins, leading to the onset and/or progression of many disease pathologies [2,3,4]. The present study is based on the hypothesis that the anti-inflammatory role of selenium occurs, in part, via 15d-PGJ2-dependent intracellular signaling pathways in macrophages and that COX-1 plays a pivotal role in the control of NF-B activity
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