MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB
MAPK Kinase 3 Potentiates Chlamydia HSP60-Induced Inflammatory Response through Distinct Activation of NF-κB
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DOI：
10.4049/jimmunol.1300481
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Shi, Liyun
中科院分区：
文献类型：
--
作者：
Kang, Yanhua;Wang, Fang;Shi, Liyun
肺炎衣原体（C.肺炎）仍然是细菌性肺炎的主要原因之一，并且与一些炎症相关疾病如哮喘、慢性阻塞性肺病和血管疾病的发病机制有关。热休克蛋白60是C.与炎症性疾病密切相关的肺炎。然而，衣原体热休克蛋白（cHSP 60）的免疫病理学特性的分子基础尚未阐明。在这篇文章中，我们报告，MAPK激酶3（MKK 3）是必不可少的cHSP 60诱导的肺部炎症，因为MKK 3基因敲除小鼠表现出显着减少肺中性粒细胞的积累和减少的促炎介质的产生，与减轻肺组织的炎症反应。从机制上讲，p38激酶被MKK 3选择性激活，以响应cHSP 60和激活NF-κ B B，通过刺激核激酶，促分裂原和应激活化蛋白激酶1。在巨噬细胞中特异性敲低丝裂原和应激活化蛋白激酶1导致NF-κ B B/RelA在Ser（276）的磷酸化缺陷，但对RelA易位没有明显影响。此外，发现TGF-β激活的激酶1将信号从TLR 4传递到MKK 3，TLR 4是在炎症反应的起始中感知cHSP 60的主要受体。因此，我们确定了MKK 3信号在cHSP 60病理学中的关键作用，并提出了一种新的机制。肺炎相关的炎性疾病。
Chlamydia pneumonia (C. pneumonia) remains one of the leading causes of bacterial pneumonia and has been implicated in the pathogenesis of some inflammation-related diseases, such as asthma, chronic obstructive pulmonary disease, and vascular diseases. Heat shock protein 60 is one of the pathogenic components of C. pneumonia that is closely associated with the inflammatory disorders. However, the molecular basis for the immunopathologic property of chlamydial heat shock protein (cHSP60) has not been elucidated. In this article, we report that MAPK kinase 3 (MKK3) is essential for cHSP60-induced lung inflammation, because MKK3-knockout mice displayed significantly reduced lung neutrophil accumulation and decreased production of proinflammatory mediators, correlating with the alleviated inflammatory response in lung tissues. Mechanistically, p38 kinase was selectively activated by MKK3 in response to cHSP60 and activated NF-kappa B by stimulating the nuclear kinase, mitogen-and stress-activated protein kinase 1. The specific knockdown of mitogen- and stress-activated protein kinase 1 in macrophages resulted in a defective phosphorylation of NF-kappa B/RelA at Ser(276) but had no apparent effect on RelA translocation. Furthermore, TGF-beta-activated kinase 1 was found to relay the signal to MKK3 from TLR4, the major receptor that sensed cHSP60 in the initiation of the inflammatory response. Thus, we establish a critical role for MKK3 signaling in cHSP60 pathology and suggest a novel mechanism underlying C. pneumonia-associated inflammatory disorders.