Porphyromonas gingivalis fimbria-dependent activation of inflammatory genes in human aortic endothelial cells
Porphyromonas gingivalis fimbria-dependent activation of inflammatory genes in human aortic endothelial cells
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DOI：
10.1128/iai.73.9.5367-5378.2005
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发表时间：
2005-09-01
影响因子：
3.1
通讯作者：
Genco, CA
中科院分区：
文献类型：
--
作者：
Chou, HH;Yumoto, H;Genco, CA
流行病学和病理学研究表明，口腔病原体牙龈卟啉单胞菌的感染可以增强动脉粥样硬化和人类冠心病。此外，已证明感染侵入性而非侵入性牙龈卟啉单胞菌会加速载脂蛋白E缺陷（ApoE（-/-））小鼠的动脉粥样硬化，并加速主动脉组织中的局部炎症反应。在本研究中，使用高密度寡核苷酸芯片，我们已经确定了人类主动脉内皮细胞（HAEC）感染后的侵袭性和非侵袭性牙龈卟啉单胞菌的基因表达谱。在用侵袭性牙龈卟啉单胞菌菌株381感染HAEC后，我们观察到68个基因的上调。与未感染的HAEC对照相比，编码细胞因子Gro 2和Gro 3的基因;粘附分子细胞间粘附分子1（ICAM-1）、血管细胞粘附分子（VCAM）-1和ELAM-1（E-选择素）;趋化因子白细胞介素-8（IL-8）;以及促炎分子IL-6和环氧合酶-2是牙龈卟啉单胞菌381感染的HAEC中最高度上调的基因。还观察到信号分子、转录调节因子和细胞表面受体的mRNA水平增加。值得注意的是，这68个基因中只有4个在感染非侵入性牙龈卟啉单胞菌fimA突变体的HAEC中也上调。逆转录-PCR、酶联免疫吸附试验和荧光激活细胞分选分析证实了ICAM-1、VCAM-1、E-/P-选择素、IL-6和IL-8在侵袭性牙龈卟啉单胞菌感染的HAEC中的表达。我们还通过免疫组织化学分析证明，在用侵袭性牙龈卟啉单胞菌经口攻击的ApoE-/-小鼠的主动脉组织中ICAM-1和VCAM-1的表达增加，但用非侵袭性牙龈卟啉单胞菌fimA突变体则没有。总之，这些结果表明牙龈卟啉单胞菌菌毛介导的侵袭上调HAEC和主动脉组织中的炎症基因表达，并表明侵袭性牙龈卟啉单胞菌感染直接加速主动脉中的炎症反应。
Epidemiological and pathological studies have suggested that infection with the oral pathogen Porphyromonas gingivalis can potentiate atherosclerosis and human coronary heart disease. Furthermore, infection with invasive, but not noninvasive P. gingivalis has been demonstrated to accelerate atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice and to accelerate local inflammatory responses in aortic tissue. In the present study, using high-density oligonucleotide microarrays, we have defined the gene expression profile of human aortic endothelial cells (HAEC) after infection with invasive and noninvasive P. gingivalis. After infection of HAEC with invasive P. gingivalis strain 381, we observed the upregulation of 68 genes. Genes coding for the cytokines Gro2 and Gro3; the adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and ELAM-1 (E-selectin); the chemokine interleukin-8 (IL-8); and the proinflammatory molecules IL-6 and cyclooxygenase-2 were among the most highly upregulated genes in P. gingivalis 381-infected HAEC compared to uninfected HAEC control. Increased mRNA levels for signaling molecules, transcriptional regulators, and cell surface receptors were also observed. Of note, only 4 of these 68 genes were also upregulated in HAEC infected with the noninvasive P. gingivalis fimA mutant. Reverse transcription-PCR, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorting analysis confirmed the expression of ICAM-1, VCAM-1, E-/P-selectins, IL-6, and IL-8 in HAEC infected with invasive P. gingivalis. We also demonstrated that increased expression of ICAM-1 and VCAM-1 in aortic tissue of ApoE-/- mice orally challenged with invasive P. gingivalis but not with the noninvasive P. gingivalis fimA mutant by immunohistochemical analysis. Taken together, these results demonstrate that P. gingivalis fimbria-mediated invasion upregulates inflammatory gene expression in HAEC and in aortic tissue and indicates that invasive P. gingivalis infection accelerates inflammatory responses directly in the aorta.