Ishikawa Eri, Nakazawa Masatoshi, Yoshinari Masahiro, Minami Mutsuhiko
Department of Immunology, Yokohama City University School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan.
J Virol. 2005 Jun;79(12):7658-63. doi: 10.1128/JVI.79.12.7658-7663.2005.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of various tumor cells but not normal cells. However, various cytokines and virus infection differentially regulate TRAIL and TRAIL receptor expression. It has been demonstrated that virus infection changes the pattern of human TRAIL-receptor expression on normal cells, which were resistant to TRAIL-mediated apoptosis, and makes them susceptible to TRAIL-mediated apoptosis. Since previous studies on the function of TRAIL have been performed mainly in vitro, its physiological role in the immune response to virus infection remains unknown. In the present study, we investigated the expression of TRAIL in the lungs of influenza virus-infected mice and the function of TRAIL in the immune response to infection. Influenza virus infection increased TRAIL mRNA expression in the lung. TRAIL protein expression was induced on NK cells in the lung 4 days after infection. At 7 days after infection, TRAIL protein expression was also detected on CD4(+) and CD8(+) T cells. However, NK cells and T cells in the lungs of uninfected mice did not express a detectable level of TRAIL on their cell surfaces. DR5, which is a mouse TRAIL receptor, was also induced to express after virus infection. Expression of both TRAIL and DR5 mRNAs was reduced to normal level at 6 weeks after virus infection. Administration of anti-TRAIL monoclonal antibody, which blocks TRAIL without killing TRAIL-expressing cells, to mice during influenza virus infection significantly delayed virus clearance in the lung. These results suggest that TRAIL plays an important role in the immune response to virus infection.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导多种肿瘤细胞凋亡，但对正常细胞无此作用。然而，多种细胞因子和病毒感染对TRAIL及其受体的表达有不同的调节作用。已有研究表明，病毒感染可改变正常细胞上人类TRAIL受体的表达模式，这些正常细胞原本对TRAIL介导的凋亡具有抗性，而病毒感染后使其对TRAIL介导的凋亡变得敏感。由于以往关于TRAIL功能的研究主要在体外进行，其在病毒感染免疫反应中的生理作用尚不清楚。在本研究中，我们调查了流感病毒感染小鼠肺组织中TRAIL的表达情况以及TRAIL在感染免疫反应中的功能。流感病毒感染可增加肺组织中TRAIL mRNA的表达。感染后4天，肺组织中的自然杀伤细胞（NK细胞）上可诱导出TRAIL蛋白表达。感染后7天，在CD4(+)和CD8(+) T细胞上也检测到TRAIL蛋白表达。然而，未感染小鼠肺组织中的NK细胞和T细胞在其细胞表面未表达可检测水平的TRAIL。小鼠TRAIL受体DR5在病毒感染后也被诱导表达。病毒感染6周后，TRAIL和DR5 mRNA的表达均恢复至正常水平。在流感病毒感染期间，给小鼠注射抗TRAIL单克隆抗体（该抗体可阻断TRAIL但不杀伤表达TRAIL的细胞），可显著延迟肺组织中病毒的清除。这些结果表明，TRAIL在病毒感染的免疫反应中发挥重要作用。
