The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages

Abstract

Physiological selenium (Se) levels counteract excessive inflammation, with selenoproteins shaping the immunoregulatory cytokine and lipid mediator profile. How exactly differentiation of monocytes into macrophages influences the expression of the selenoproteome in concert with the Se supply remains obscure. THP-1 monocytes were differentiated with phorbol 12-myristate 13-acetate (PMA) into macrophages and (i) the expression of selenoproteins, (ii) differentiation markers, (iii) the activity of NF-κB and NRF2, as well as (iv) lipid mediator profiles were analyzed. Se and differentiation affected the expression of selenoproteins in a heterogeneous manner. GPX4 expression was substantially decreased during differentiation, whereas GPX1 was not affected. Moreover, Se increased the expression of selenoproteins H and F, which was further enhanced by differentiation for selenoprotein F and diminished for selenoprotein H. Notably, LPS-induced expression of NF-κB target genes was facilitated by Se, as was the release of COX- and LOX-derived lipid mediators and substrates required for lipid mediator biosynthesis. This included TXB2, TXB3, 15-HETE, and 12-HEPE, as well as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Our results indicate that Se enables macrophages to accurately adjust redox-dependent signaling and thereby modulate downstream lipid mediator profiles.

Hydroxy-Selenomethionine, an Organic Selenium Source, Increases Selenoprotein Expression and Positively Modulates the Inflammatory Response of LPS-Stimulated Macrophages

“…Moreover, Verstovsek et al [ 49 ] observed an increase in autofluorescence in splenic macrophages stimulated with LPS as Sköld et al [ 50 ] and Pankow et al [ 51 ] observed in alveolar macrophages due to the presence of higher amounts of ROS as well as higher metabolic activity and Edelson et al [ 52 ] due to the formation of protein adducts. Furthermore, autofluorescence is associated with macrophage activation [ 53 ] and with cytokine production, such as IL-1α [ 54 ].…”

Relationship between selenium status, selenoproteins and COVID-19 and other inflammatory diseases: A critical review

“…In a recent study, Wolfram et al [108] demonstrated that Se did not modulate the differentiation of human THP-1 leukemic monocytes into macrophages after treatment with phorbol myristate acetate (PMA). However, protein levels of GPX4, SELENOH, SELENOS and selenoprotein F (SELENOF) increased after selenite inclusion in the cell culture medium.…”

“…In accordance, Se-deficiency disrupted selenoprotein mRNA synthesis and caused immunological impairments in the thymus and spleen of chickens [99] , [149] . Nonetheless, it is important to emphasize that the changes in mRNA of selenoproteins do not always correlate with the changes in the selenoproteins expression [108] . Consequently, it would be essential to perform both selenotranscriptome and selenoproteome integrated analyses in models of insufficient, sufficient, excess and toxic levels of Se and determine how they correlated with inflammatory markers (including lipidomic analyses of lipid mediators of inflammation) and cellular immunological responses.…”

Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

“…In this context, the expression of two other (ferroptosis-related) NRF2 target genes, GPX4 and SLC7A11, is decreased by 55 in cell-based studies (at low concentrations) 220 and in tumors from murine xenografts. 222 Such an opposing regulation of SLC7A11 and GPX4 relative to major NRF2 target genes (GCLC, GCL modifier subunit [GCLM], NAD(P)H quinone dehydrogenase 1 [NQO1], HO-1) has, however, previously been observed, for example, for phorbol 12-myristate 13-acetate (PMA)-treated human THP-1 monocytic leukemia cells, 224 and is not necessarily an indicator for NRF2 inhibition.…”