TLR4型
p38丝裂原活化蛋白激酶
糖皮质激素受体
MAPK/ERK通路
生物
糖皮质激素
Toll样受体
先天免疫系统
细胞因子
蛋白激酶B
细胞生物学
激酶
信号转导
脂多糖
内分泌学
免疫系统
免疫学
作者
Somnath Bhattacharyya,Diane E. Brown,Judson A. Brewer,Sherri K. Vogt,Louis J. Muglia
出处
期刊:Blood
[American Society of Hematology]
日期:2007-01-25
卷期号:109 (10): 4313-4319
被引量:211
标识
DOI:10.1182/blood-2006-10-048215
摘要
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.
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