The Anti-inflammatory Effects of Selenium Are Mediated through 15-Deoxy-Δ12,14-prostaglandin J2 in Macrophages

Abstract

Selenium is an essential micronutrient that suppresses the redox-sensitive transcription factor NF-B-dependent proinflammatory 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-B cascade, IB-kinase ␤ (IKK␤) 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␤ in lipopolysaccharide (LPS)-treated macrophages. Stimulation by LPS of seleniumsupplemented macrophages resulted in a time-dependent increase in 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) formation, an endogenous inhibitor of IKK␤ activity. Further analysis revealed that inhibition of IKK␤ activity in seleniumsupplemented cells correlated with the Michael addition product of 15d-PGJ 2 with Cys-179 of IKK␤, 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-␥ 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-PGJ 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.

Selenoproteins: Molecular Pathways and Physiological Roles

“…Moreover, characterization of the recently developed SelK knockout mouse model demonstrated that SelK deficiency leads to deficient Ca 2ϩ flux during immune cell activation and impaired immune response (358). These findings suggest that SelK and SelS might mediate the anti-inflammatory effects of Se and its role in the immune system (265,361). However, the molecular mechanisms by which SelS and SelK affect immune function and inflammatory response await further investigation.…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…However, elegant experiments involving mouse bone marrow-derived macrophages (BMDM) and RAW 264.7 mouse macrophages revealed an important, albeit complex effect of altered cellular Se status and NFjB activation. In these studies, BMDM were isolated from mice fed Se-deficient and Se-supplemented diets containing 0.01 or 0.4 ppm Se as described (174,259). BMDM and RAW 264.7 cells were cultured in media containing 5% defined FBS with total Se of 6.0 nM (low Se) or the same media supplemented with 2 lM Se (high Se).…”

Dietary manipulation in musculoskeletal conditions

“…-GPxs can modulate the production of biologically active eicosanoids by the COX and LOX pathways [74]. -Se down-regulates the expression of inflammatory genes [75].…”