Lim Jae Hyang, Stirling Brigid, Derry Jonathan, Koga Tomoaki, Jono Hirofumi, Woo Chang-Hoon, Xu Haodong, Bourne Patricia, Ha Un-Hwan, Ishinaga Hajime, Xu Haidong, Andalibi Ali, Feng Xin-Hua, Zhu Hongguang, Huang Yuxian, Zhang Wenhong, Weng Xinhua, Yan Chen, Yin Zhinan, Briles David E, Davis Roger J, Flavell Richard A, Li Jian-Dong
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Immunity. 2007 Aug;27(2):349-60. doi: 10.1016/j.immuni.2007.07.011.
Streptococcus pneumoniae (S. pneumoniae) causes high early mortality in pneumococcal pneumonia, which is characterized by acute lung injury (ALI). The molecular mechanisms underlying ALI and the high early mortality remain unknown. Despite recent studies that identify deubiquitinating enzyme cylindromatosis (CYLD) as a key regulator for T cell development, tumor cell proliferation, and NF-kappaB transcription factor signaling, its role in regulating bacteria-induced lethality, however, is unknown. Here, we showed that CYLD deficiency protected mice from S. pneumoniae pneumolysin (PLY)-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia.
肺炎链球菌可导致肺炎球菌肺炎早期高死亡率，其特征为急性肺损伤（ALI）。ALI及早期高死亡率背后的分子机制尚不清楚。尽管近期研究确定去泛素化酶圆柱瘤蛋白（CYLD）是T细胞发育、肿瘤细胞增殖及核因子κB转录因子信号传导的关键调节因子，但其在调节细菌诱导的致死率方面的作用仍不清楚。在此，我们表明CYLD缺陷可保护小鼠免受肺炎链球菌溶血素（PLY）诱导的ALI和致死率影响。PLY可高度诱导CYLD，且CYLD抑制肺中纤溶酶原激活物抑制剂-1（PAI-1）的MKK3-p38激酶依赖性表达，从而加重ALI和死亡率。因此，CYLD对宿主存活有害，从而揭示了肺炎球菌肺炎早期高死亡率的潜在机制。
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