p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation
p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation
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DOI：
10.1073/pnas.1207290109
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发表时间：
2012-07-10
影响因子：
11.1
通讯作者：
Cuenda, Ana
中科院分区：
文献类型：
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作者：
Risco, Ana;del Fresno, Carlos;Cuenda, Ana
主要在药理学实验的基础上，p38 α MAP激酶亚型已被确定为免疫和炎症反应的重要调节剂。然而，相关的p38 γ和p38 δ激酶的作用仍不清楚。在这里，我们表明，p38 γ和p38 δ的缺失损害了先天性免疫反应的脂多糖（LPS），Toll样受体4（TLR 4）配体，通过阻断细胞外信号调节激酶1/2（ERK 1/2）激活巨噬细胞和树突状细胞。p38 γ和p38 δ是维持肿瘤进展位点2（TPL 2）的稳态水平所必需的，TPL 2是TLR 4刺激后介导ERK 1/2活化的MKK激酶。在LPS刺激的p38 γ/δ缺失小鼠巨噬细胞中，TNF α、IL-1 β和IL-10的产生减少，而IL-1/2和IFN β的产生增加，这与TPL 2/ERK 1/2信号传导对这些细胞因子诱导的已知作用一致。此外，p38 γ/δ缺陷小鼠对LPS诱导的脓毒性休克的敏感性低于对照组，在激发后显示出较低的TNF α和IL-1 β水平。总之，我们的研究结果建立了p38 γ和p38 δ作为先天免疫反应的关键组成部分。
On the basis mainly of pharmacological experiments, the p38 alpha MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38 gamma and p38 delta kinases has remained unclear. Here, we show that deletion of p38 gamma and p38 delta impaired the innate immune response to lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand, by blocking the extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages and dendritic cells. p38 gamma and p38 delta were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNF alpha, IL-1 beta, and IL-10 production were reduced in LPS-stimulated macrophages from p38 gamma/delta-null mice, whereas IL-12 and IFN beta production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38 gamma/delta-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNF alpha and IL-1 beta levels after challenge. Together, our results establish p38 gamma and p38 delta as key components in innate immune responses.