Macrophage glucocorticoid receptors regulate toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase
Macrophage glucocorticoid receptors regulate toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase
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DOI：
10.1182/blood-2006-10-048215
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发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
Muglia, Louis J.
中科院分区：
文献类型：
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作者：
Bhattacharyya, Sandip;Brown, Diane E.;Muglia, Louis J.
为了探索糖皮质激素在先天免疫应答中调控激酶通路中的作用，我们在巨噬细胞（MGRKO）中产生条件缺失糖皮质激素受体（GR）的小鼠。脂多糖（LPS）激活toll样受体4 （TLR4）导致MGRKO小鼠的死亡率和细胞因子的产生高于对照组。在体外，地塞米松（Dex）治疗显著抑制lps介导的炎症基因诱导，但不抑制gfi缺陷巨噬细胞。我们发现，在对照巨噬细胞中，Dex抑制p38 MAPK，但不抑制PI3K/Akt， ERK或JNK。与p38抑制相关，Dex诱导对照的MAP激酶磷酸酶-1 (MKP-1)，而不是。MGRKO,巨噬细胞。与离体研究一致，用p38 mapk特异性抑制剂治疗可使MGRKO小鼠免于lps诱导的死亡。综上所述，我们发现p38 MAPK及其下游靶点对巨噬细胞gr介导的免疫抑制至关重要。
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.