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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4313-4319. Prepublished online as a Blood First Edition Paper on January 25, 2007; DOI 10.1182/blood-2006-10-048215. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-10-048215v1 109/10/4313    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bhattacharyya, S. Articles by Muglia, L. J. Search for Related Content PubMed PubMed Citation Articles by Bhattacharyya, S. Articles by Muglia, L. J. Related Collections Immunobiology Phagocytes Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase Sandip Bhattacharyya1, Diane E. Brown1, Judson A. Brewer1, Sherri K. Vogt1, and Louis J. Muglia1,2,3 Departments of 1 Pediatrics 2 Molecular Biology and Pharmacology, and 3 Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. H. Mogensen Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses Clin. Microbiol. Rev., April 1, 2009; 22(2): 240 - 273. [Abstract] [Full Text] [PDF] K. Kamiyama, N. Matsuda, S. Yamamoto, K.-i. Takano, Y. Takano, H. Yamazaki, S.-i. Kageyama, H. Yokoo, T. Nagata, N. Hatakeyama, et al. Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L998 - L1006. [Abstract] [Full Text] [PDF] W. Wijagkanalan, Y. Higuchi, S. Kawakami, M. Teshima, H. Sasaki, and M. Hashida Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model Mol. Pharmacol., November 1, 2008; 74(5): 1183 - 1192. [Abstract] [Full Text] [PDF] A. R. Clark, J. R. S. Martins, and C. R. Tchen Role of Dual Specificity Phosphatases in Biological Responses to Glucocorticoids J. Biol. Chem., September 19, 2008; 283(38): 25765 - 25769. [Abstract] [Full Text] [PDF] Y. Zhang, X.-T. Bai, K.-Y. Zhu, Y. Jin, M. Deng, H.-Y. Le, Y.-F. Fu, Y. Chen, J. Zhu, A. T. Look, et al. In Vivo Interstitial Migration of Primitive Macrophages Mediated by JNK-Matrix Metalloproteinase 13 Signaling in Response to Acute Injury J. Immunol., August 1, 2008; 181(3): 2155 - 2164. [Abstract] [Full Text] [PDF] S. Wust, J. van den Brandt, D. Tischner, A. Kleiman, J. P. Tuckermann, R. Gold, F. Luhder, and H. M. Reichardt Peripheral T Cells Are the Therapeutic Targets of Glucocorticoids in Experimental Autoimmune Encephalomyelitis J. Immunol., June 15, 2008; 180(12): 8434 - 8443. [Abstract] [Full Text] [PDF] T. H. Mogensen, R. S. Berg, S. R. Paludan, and L. Ostergaard Mechanisms of Dexamethasone-Mediated Inhibition of Toll-Like Receptor Signaling Induced by Neisseria meningitidis and Streptococcus pneumoniae Infect. Immun., January 1, 2008; 76(1): 189 - 197. [Abstract] [Full Text] [PDF]

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