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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.
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Submitted October 3, 2006
Accepted January 17, 2007
Macrophage glucocorticoid receptors regulate Toll-like receptor-4-mediated inflammatory responses by selective inhibition of p38 MAP kinase
Sandip Bhattacharyya, Diane E. Brown, Judson A. Brewer, Sherri K. Vogt, and Louis J. Muglia*
Depts of Pediatrics, Molecular Biology & Pharmacology, and Obstetrics & Gynecology, Washington University School of Medicine, St. Louis, MO, United States
* Corresponding author; email: muglia_l{at}kids.wustl.edu.
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 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.
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