Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2

被引:114
作者
Imasato, A
Desbois-Mouthon, C
Han, JH
Kai, H
Cato, ACB
Akira, S
Li, JD
机构
[1] Univ So Calif, House Ear Inst, Gonda Dept Cell & Mol Biol, Los Angeles, CA 90057 USA
[2] Univ So Calif, Dept Otolaryngol, Los Angeles, CA 90057 USA
[3] Univ Paris 06, INSERM, U402, F-75571 Paris, France
[4] The Scripps Res Inst, Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[5] Kumamoto Univ, Dept Mol Med, Kumamoto 8620973, Japan
[6] Forschungszentrum Karlsruhe, Inst Toxicol & Genet, D-76021 Karlsruhe, Germany
[7] Osaka Univ, Microbial Dis Res Inst, Dept Host Def,Japan Sci & Technol Corp, Core Res Evolutional Sci & Technol, Suita, Osaka 5650871, Japan
关键词
D O I
10.1074/jbc.M208140200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:47444 / 47450
页数:7
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