title: Protein kinase-regulated expression and immune function of thioredoxin reductase 1 in mouse macrophages.
abstract: Macrophages exposed to lipopolysaccharide (LPS) exhibit radical changes in mRNA and protein profiles. This shift in gene expression is geared not only to activate immune effector and regulatory mechanisms, but also to adjust the immune cell's metabolism to new physiological demands. However, it remains largely unknown whether immune function and metabolic state are mutually regulatory and, if so, how they are mechanistically interrelated in macrophages. Selenium, a dietary trace element exerting pleiotropic effects on immune homeostasis, and selenium-containing proteins (selenoproteins) may play a role in such coordination. We examined the incorporation of radiolabeled selenium into protein during LPS stimulation, and identified thioredoxin reductase 1 (TR1) as the only LPS-inducible selenoprotein in macrophages. TR1 induction occurred at the transcriptional level and depended on the intracellular signaling pathways mediated by p38 MAP kinase and IκB kinase. Macrophage-specific ablation of TR1 in mice resulted in a drastic decrease in the expression of VSIG4, a B7 family protein known to suppress T cell activation. These results reveal TR1 as both a regulator and a regulated target in the macrophage gene expression network, and suggest a link between selenium metabolism and immune signaling.
authors.affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Min-Hyuk
authors.initials: MH
authors.lastname: Yoo
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D000818:Animals; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051140:Selenoproteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D051140:Selenoproteins; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases