title: Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase.
abstract: To explore the role of glucocorticoids in regulation of kinase pathways during innate immune responses, we generated mice with conditional deletion of glucocorticoid receptor (GR) in macrophages (MGRKO). Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) caused greater mortality and cytokine production in MGRKO mice than in controls. Ex vivo, treatment with dexamethasone (Dex) markedly inhibited LPS-mediated induction of inflammatory genes in control but not GR-deficient macrophages. We show that Dex inhibits p38 MAPK, but not PI3K/Akt, ERK, or JNK, in control macrophages. Associated with p38 inhibition, Dex induced MAP kinase phosphatase-1 (MKP-1) in control, but not MGRKO, macrophages. Consistent with the ex vivo studies, treatment with a p38 MAPK-specific inhibitor resulted in rescue of MGRKO mice from LPS-induced lethality. Taken together, we identify p38 MAPK and its downstream targets as essential for GR-mediated immunosuppression in macrophages.
authors.affiliation: Departments of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Sandip
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Diane E
authors.initials: DE
authors.lastname: Brown
authors.forename: Judson A
authors.initials: JA
authors.lastname: Brewer
authors.forename: Sherri K
authors.initials: SK
authors.lastname: Vogt
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases