Ability of IDO To Attenuate Liver Injury in α-Galactosylceramide-Induced Hepatitis Model
Ability of IDO To Attenuate Liver Injury in α-Galactosylceramide-Induced Hepatitis Model
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DOI：
10.4049/jimmunol.0904173
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发表时间：
2010-10-15
影响因子：
4.4
通讯作者：
Seishima, Mitsuru
中科院分区：
文献类型：
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作者：
Ito, Hiroyasu;Hoshi, Masato;Seishima, Mitsuru
IDO将色氨酸转化为L-犬尿氨酸，并被认为是促进耐受和抑制获得性免疫的相关分子。在这项研究中，我们研究了IDO在α-半乳糖基神经酰胺(α-GalCer)诱导的肝炎中的作用。实时定量聚合酶链式反应、免疫印迹和免疫组织化学分析证实，给予α-GalCer的野生型(WT)小鼠肝脏中IDO表达增加。IDO基因敲除(KO)小鼠注射α-GalCer后，血清丙氨酸氨基转移酶水平明显高于WT小鼠。1-甲基-D-色氨酸也加重了小鼠肝炎模型的肝损伤。在α-GalCer诱导的肝炎模型中，肿瘤坏死因子-α在肝损伤的发生发展中起关键作用。与WT小鼠相比，IDO-KO小鼠肝脏中肿瘤坏死因子-α的mRNA表达和蛋白水平均显著增强。用流式细胞仪分析了经α-GalCer处理的WT小鼠和IDO-KO小鼠的肝内淋巴细胞表型，发现IDO-KO小鼠CD49b(+)和CD11b(+)细胞数量增加。此外，由于注射α-GalCer的IDO-KO小鼠肝脏中NK细胞和巨噬细胞数量的增加，这些小鼠的肿瘤坏死因子-α的分泌高于WT小鼠。IDO缺乏加重了α-GalCer诱导的肝炎的肝损伤。促炎细胞因子诱导的IDO可减少肝脏中产生肿瘤坏死因子-α的免疫细胞的数量。因此，在α-GalCer诱导的肝炎模型中，IDO可能抑制过度活跃的免疫反应。《免疫学杂志》，2010,185：4554-4560。
IDO converts tryptophan to L-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in alpha-galactosylceramide (alpha-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered alpha-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after alpha-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In alpha-GalCer-induced hepatitis models, TNF-alpha is critical in the development of liver injury. The mRNA expression and protein level of TNF-alpha in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with alpha-GalCer were analyzed by flow cytometry, and the numbers of CD49b(+) and CD11b(+) cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with alpha-GalCer, TNF-alpha secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in alpha-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-alpha-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the alpha-GalCer-induced hepatitis model. The Journal of Immunology, 2010, 185: 4554-4560.