Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
J Immunol. 2013 Jul 1;191(1):386-94. doi: 10.4049/jimmunol.1300481. Epub 2013 May 31.
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-κB 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-κB/RelA at Ser(276) but had no apparent effect on RelA translocation. Furthermore, TGF-β-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.
肺炎衣原体（C. pneumoniae）仍然是细菌性肺炎的主要原因之一，并与一些炎症相关疾病的发病机制有关，如哮喘、慢性阻塞性肺疾病和血管疾病。热休克蛋白 60 是 C. pneumoniae 的致病成分之一，与炎症紊乱密切相关。然而，衣原体热休克蛋白（cHSP60）的免疫病理特性的分子基础尚未阐明。在本文中，我们报告 MAPK 激酶 3（MKK3）是 cHSP60 诱导的肺部炎症所必需的，因为 MKK3 敲除小鼠显示肺部中性粒细胞积聚明显减少，促炎介质产生减少，与肺部组织炎症反应减轻相关。在机制上，cHSP60 选择性地激活 MKK3 上的 p38 激酶，通过刺激丝裂原和应激激活蛋白激酶 1 激活 NF-κB。巨噬细胞中丝裂原和应激激活蛋白激酶 1 的特异性敲低导致 NF-κB/RelA 在 Ser（276）上的磷酸化缺陷，但对 RelA 易位没有明显影响。此外，发现 TGF-β激活激酶 1 将信号从 TLR4 转导至 MKK3，TLR4 是在炎症反应起始时感知 cHSP60 的主要受体。因此，我们确立了 MKK3 信号在 cHSP60 病理学中的关键作用，并提出了衣原体肺炎相关炎症紊乱的新机制。
