Lin Li, Wen Shun-hang, Guo Shu-zhen, Su Xiao-yan, Wu Hu-jun, Chong Lei, Zhang Hai-lin, Zhang Wei-xi, Li Chang-chong
Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, 109 West Xueyuan Road, Lucheng District, Wenzhou, 325027, Zhejiang, People's Republic of China.
Mol Cell Biochem. 2014 Sep;394(1-2):199-208. doi: 10.1007/s11010-014-2095-2. Epub 2014 Jun 4.
Streptococcus pneumoniae is an important pathogen of pneumonia in human. Human alveolar epithelium acts as an effective barrier and is an active participant in host defense against invasion of bacterial by production of various mediators. Sirtuin 1 (SIRT1), the prototypic class III histone deacetylase, is involved in the molecular control of lifespans and immune responses. This study aimed at examining the role of SIRT1 in mediating S. pneumoniae-induced human β-defensin-2 (hBD2) and interleukin-8(IL-8) expression in the alveolar epithelial cell line A549 and the underlying mechanisms involved. A549 cells were infected with S. pneumoniae for indicated times. Exposure of A549 cells to S. pneumoniae increased the expressions of SIRT1 protein, hBD2 and IL-8 mRNA, and protein. The SIRT1 activator resveratrol enhanced S. pneumoniae-induced gene expression of hBD2 but decreased IL-8 mRNA levels. Blockade of SIRT1 activity by the SIRT1 inhibitors nicotinamide reduced S. pneumoniae-induced hBD2 mRNA expression but increased its stimulatory effects on IL-8 mRNA. S. pneumoniae-induced activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). SIRT1 expression was attenuated by selective inhibitors of ERK and p38 MAPK. The hBD2 mRNA production was decreased by pretreatment with p38 MAPK inhibitor but not with ERK inhibitor, whereas the IL-8 mRNA expression was controlled by phosphorylation of ERK. These results suggest that SIRT1 mediates the induction of hBD2 and IL-8 gene expression levels in A549 cell by S. pneumoniae. SIRT1 may play a key role in host immune and defense response in A549.
肺炎链球菌是人类肺炎的重要病原体。人肺泡上皮细胞是一道有效的屏障，通过产生各种介质积极参与宿主抵御细菌入侵的防御过程。沉默调节蛋白1（SIRT1）是Ⅲ类组蛋白去乙酰化酶的原型，参与寿命和免疫反应的分子调控。本研究旨在探讨SIRT1在介导肺炎链球菌诱导肺泡上皮细胞系A549中人类β-防御素-2（hBD2）和白细胞介素-8（IL-8）表达中的作用及其潜在机制。将A549细胞用肺炎链球菌感染指定时间。A549细胞暴露于肺炎链球菌后，SIRT1蛋白、hBD2和IL-8 mRNA及蛋白的表达增加。SIRT1激活剂白藜芦醇增强了肺炎链球菌诱导的hBD2基因表达，但降低了IL-8 mRNA水平。SIRT1抑制剂烟酰胺阻断SIRT1活性，降低了肺炎链球菌诱导的hBD2 mRNA表达，但增强了其对IL-8 mRNA的刺激作用。肺炎链球菌诱导细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）激活。ERK和p38 MAPK的选择性抑制剂使SIRT1表达减弱。用p38 MAPK抑制剂预处理可降低hBD2 mRNA产生，但用ERK抑制剂则不能，而IL-8 mRNA表达受ERK磷酸化调控。这些结果表明，SIRT1介导肺炎链球菌诱导A549细胞中hBD2和IL-8基因表达水平。SIRT1可能在A549细胞的宿主免疫和防御反应中起关键作用。
