Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone

• Published in: Scientific reports 2014-03, Vol.4 (1), p.4323, Article 4323
• Main Authors: Haim, Yasmin Ohana, Unger, Naamit Deshet, Souroujon, Miriam C., Mittelman, Moshe, Neumann, Drorit
• Format: Article
• Language: English
• Subjects: 631/250/2504/342; 631/250/256/1980; Alternative splicing; Animals; Antigens, Differentiation - metabolism; Apoptosis; Apoptosis - drug effects; Bone marrow; Bone Marrow Cells - cytology; CD11b antigen; CD11b Antigen - metabolism; Cell death; Cell surface; Chemokine CCL3 - genetics; Chemokine CCL3 - metabolism; Dexamethasone; Dexamethasone - toxicity; Endotoxins; Female; Glucocorticoids; Glucocorticoids - toxicity; Humanities and Social Sciences; Immune system; Inflammation; Leucine zipper proteins; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophage inflammatory protein; Macrophage inflammatory protein 1; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; RNA, Messenger - metabolism; Science; Sepsis; Steroids; Surface markers; Transcription; Up-Regulation - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep04323

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.