Ogiso Hideyuki, Ito Hiroyasu, Kanbe Ayumu, Ando Tatsuya, Hara Akira, Shimizu Masahito, Moriwaki Hisataka, Seishima Mitsuru
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
Dig Dis Sci. 2017 Sep;62(9):2386-2396. doi: 10.1007/s10620-017-4651-6. Epub 2017 Jun 21.
The inflammatory response accelerates early liver regeneration after liver injury and resection. Recent studies have demonstrated that indoleamine 2,3-dioxygenase-1 (IDO1) suppresses the activation of inflammatory cells and induces immune tolerance. In this study, we examined the role of IDO1 in liver regeneration after partial hepatectomy (PHx).
WT or IDO1-knockout (IDO1-KO) mice received 70% PHx. The liver-body weight ratio after PHx was measured and hepatocyte growth was assessed by immunostaining. The expression of cell cycle genes and pro-inflammatory cytokines in the liver was analyzed by quantitative RT-PCR. In addition, 1-methyl-DL-tryptophan (1-MT), which is an IDO1 inhibitory agent, was given to WT mice and the liver-body weight ratio was measured after PHx.
The liver-body weight ratio was significantly increased in IDO1-KO mice compared with that in WT mice after PHx. More Ki-67-positive cells were present in IDO1-KO mice than in WT mice after PHx. The expression of cell cycle genes (cyclin D1, cyclin E) and pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) was up-regulated in the remnant liver of IDO1-KO mice compared with WT mice. Moreover, treatment with 1-MT promoted liver regeneration.
IDO1 deficiency promoted early liver regeneration after PHx, indicating that IDO1 suppresses the production of inflammatory cytokines and subsequently inhibits hepatocyte proliferation during liver regeneration.
炎症反应可加速肝损伤和肝切除术后的早期肝脏再生。近期研究表明，吲哚胺2,3-双加氧酶-1（IDO1）可抑制炎症细胞的活化并诱导免疫耐受。在本研究中，我们探讨了IDO1在部分肝切除（PHx）后肝脏再生中的作用。
野生型（WT）或IDO1基因敲除（IDO1-KO）小鼠接受70% PHx手术。测量PHx术后肝脏与体重之比，并通过免疫染色评估肝细胞生长情况。采用定量逆转录聚合酶链反应（RT-PCR）分析肝脏中细胞周期基因和促炎细胞因子的表达。此外，给野生型小鼠注射IDO1抑制剂1-甲基-DL-色氨酸（1-MT），并测量PHx术后肝脏与体重之比。
与野生型小鼠相比，IDO1-KO小鼠在PHx术后肝脏与体重之比显著增加。PHx术后，IDO1-KO小鼠中Ki-67阳性细胞比野生型小鼠更多。与野生型小鼠相比，IDO1-KO小鼠残余肝脏中细胞周期基因（细胞周期蛋白D1、细胞周期蛋白E）和促炎细胞因子（IL-1β、TNF-α和IL-6）的表达上调。此外，1-MT治疗可促进肝脏再生。
IDO1缺乏促进了PHx术后的早期肝脏再生，表明IDO1在肝脏再生过程中抑制炎症细胞因子的产生，进而抑制肝细胞增殖。
