Journal
BLOOD
Volume 109, Issue 10, Pages 4313-4319Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-10-048215
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Funding
- NIAID NIH HHS [AI50655, R21 AI050655, R01 AI050655] Funding Source: Medline
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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 GFI-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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