title: Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone.
abstract: Glucocorticoids (GC) display pleiotropic effects on the immune system. Macrophages are a major target for GC action. Here we show that dexamethasone (DEX), a synthetic GC, decreased viability of naïve bone marrow-derived macrophages (BMDM), involving an apoptotic mechanism. Administration of DEX together with lipopolysaccharide (LPS) protected BMDM against DEX-mediated cell death, suggesting that activated BMDM respond to DEX differently than naïve BMDM. An insight to the molecular basis of LPS actions was provided by a 7 fold increase in mRNA levels of glucocorticoid receptor beta (GRβ), a GR dominant-negative splice variant which inhibits GRα's transcriptional activity. LPS did not inhibit all DEX-mediated effects on BMDM; DEX significantly reduced the percentage of BMDM expressing high levels of the cell surface markers F4/80 and CD11b and led to a decrease in macrophage inflammatory protein 1 alpha (MIP1-α) mRNA and protein levels. These two DEX-mediated effects were not prevented by LPS. Our finding that LPS did not reduce the DEX-induced elevation of glucocorticoid-induced leucine zipper (GILZ), a mediator of GCs anti-inflammatory actions, may provide an underlying mechanism. These findings enable a better understanding of clinical states, such as sepsis, in which macrophages are activated by endotoxins and treatment by GCs is considered.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978.
authors.forename: Yasmin Ohana
authors.initials: YO
authors.lastname: Haim
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978.
authors.forename: Naamit Deshet
authors.initials: ND
authors.lastname: Unger
authors.affiliation: Department of Natural Sciences, The Open University of Israel, 1 University Rd, Raanana 43107, Israel.
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Souroujon
authors.affiliation: Department of Medicine A, Tel Aviv Sourasky Medical Center, Tel Aviv 64239; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978.
authors.forename: Moshe
authors.initials: M
authors.lastname: Mittelman
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978.
authors.forename: Drorit
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity*; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D054405:Chemokine CCL3; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; C036763:monocyte-macrophage differentiation antigen; D003907:Dexamethasone