Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2
Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2
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DOI：
10.1074/jbc.m208140200
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发表时间：
2002-12-06
影响因子：
4.8
通讯作者：
Li, JD
中科院分区：
文献类型：
--
作者：
Imasato, A;Desbois-Mouthon, C;Li, JD
尽管糖皮质激素在抑制免疫和炎症反应方面很重要，但它们在增强宿主免疫和防御入侵细菌反应中的作用却知之甚少。我们最近证实糖皮质激素协同增强非分型流感嗜血杆菌(NTHi)诱导的Toll样受体2(TLR2)的表达，TLR2是一个重要的TLR家族成员，已被证明在宿主免疫和防御反应中发挥关键作用。然而，糖皮质激素促进TLR2诱导的分子机制仍不清楚。在这里，我们显示糖皮质激素通过特异性上调MAPK磷酸酶-1(MKP-1)而协同增强NTHi诱导的TLR2的表达，进而导致TLR2表达的负调控因子p38MAPK的去磷酸化和失活。此外，TLR2在上皮细胞中的表达增加，大大增强了NTHi诱导的几种关键细胞因子的表达，包括肿瘤坏死因子-a和白介素1β和8，从而显著促进了宿主的免疫和防御反应。这些研究可能会为糖皮质激素在细菌感染时协调和优化宿主免疫和防御反应中的新角色带来新的见解，并加深我们对糖皮质激素介导的MAPK减弱的信号机制的理解。
Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. We have demonstrated recently that glucocorticoids synergistically enhance nontypeable Haemophilus influenzae (NTHi)-induced expression of Toll-like receptor 2 (TLR2), an important TLR family member that has been shown to play a critical role in host immune and defense response. However, the molecular mechanisms underlying the glucocorticoid-mediated enhancement of TLR2 induction still remain unknown. Here we show that glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAPK phosphatase-1 (MKP-1) that, in turn, leads to dephosphorylation and inactivation of p38 MAPK, the negative regulator for TLR2 expression. Moreover, increased expression of TLR2 in epithelial cells greatly enhances the NTHi-induced expression of several key cytokines, including tumor necrosis factor-a and interleukins 1beta and 8, thereby contributing significantly to host immune and defense response. These studies may bring new insights into the novel role of glucocorticoids in orchestrating and optimizing host immune and defense responses during bacterial infections and enhance our understanding of the signaling mechanisms underlying the glucocorticoid-mediated attenuation of MAPKs.