Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo
Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo
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DOI：
10.1111/j.1478-3231.2008.01748.x
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发表时间：
2009-02-01
影响因子：
6.7
通讯作者：
Seishima, Mitsuru
中科院分区：
文献类型：
--
作者：
Iwamoto, Naoki;Ito, Hiroyasu;Seishima, Mitsuru
吲哚-2，3-双加氧酶(IDO)是一种色氨酸分解代谢酶，可抑制T细胞功能和免疫耐受。在乙肝病毒转基因(TG)小鼠中，过继转移HBV特异性细胞毒性T淋巴细胞(CTL)会导致一种组织学上类似于人类急性病毒性肝炎的坏死性炎症性肝病。本研究旨在检测急性肝炎模型小鼠肝脏和肝细胞中IDO的表达。方法：用HBV特异性CTL诱导的HBVtg小鼠，随时间推移测定血清L犬尿氨酸(L-Kyn)浓度，以及血清丙氨酸转氨酶(ALT)水平。此外，我们通过免疫组织化学和逆转录聚合酶链式反应检测了注射CTL后HBVTg小鼠全肝和分离的肝细胞中IDO的表达。在HBVtg小鼠中，HBV特异性CTL在几天的过程中诱导了血清Ido-Kyn水平的慢性升高，这与肝脏Ido活性的持续增强有关。特别是，在免疫组织化学分析和逆转录-聚合酶链式反应中，注射乙肝病毒特异性CTL后，IDO在肝实质细胞(肝细胞)中的表达均增强。此外，小鼠重组干扰素-γ可直接上调原代培养肝细胞IDO的表达，细胞毒性T细胞转导导致IDO表达上调，从而可能下调T细胞的反应性。我们的发现为急性致死性肝炎小鼠肝细胞自身表达IDO和增加血中L-京水平提供了证据。这些数据表明，在促炎症细胞因子，特别是干扰素-γ的作用下，乙肝病毒感染促进了IDO的诱导。
Indoleamine-2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme inducing suppression of T-cell function and immune tolerance. In hepatitis B virus (HBV) transgenic (Tg) mice, the adoptive transfer of HBV-specific cytotoxic T lymphocytes (CTL) causes a necroinflammatory liver disease that is histologically similar to acute viral hepatitis in man. The present study aimed to determine IDO expression in the liver and hepatocytes during an acute hepatitis model.Serum l-kynurenine (l-Kyn) concentration in HBV Tg mice administered with HBV-specific CTL was measured over time, together with serum levels of alanine aminotransferase (ALT). Furthermore, we examined the expression of IDO in the total liver and isolated hepatocytes of HBV Tg mice after CTL injection using immunohistochemical analysis and reverse-transcription polymerase chain reaction (PCR).In HBV Tg mice, HBV-specific CTL induced, over the course of several days, a chronic increase in serum l-Kyn levels, which was associated with a sustained enhancement of liver IDO activity. In particular, IDO expression was enhanced in the liver parenchymal cells (hepatocytes) after HBV-specific CTL injection both in immunohistochemical analysis and in reverse-transcription PCR. Moreover, murine recombinant interferon-gamma (IFN-gamma) directly increased the IDO expression in primary hepatocytes in vitro.Cytotoxic T lymphocytes transduction results in the upregulation of IDO, which might downregulate T-cell responsiveness. Our findings provide evidence that hepatocyte itself expresses IDO and increases levels of l-Kyn in the blood in acute lethal hepatitis of mice. These data indicate that HBV infection facilitates the induction of IDO in response to proinflammatory cytokines, particularly IFN-gamma.