Watcharanurak K, Zang L, Nishikawa M, Yoshinaga K, Yamamoto Y, Takahashi Y, Ando M, Saito K, Watanabe Y, Takakura Y
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Department of Human Health Science, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan.
Gene Ther. 2014 Sep;21(9):794-801. doi: 10.1038/gt.2014.54. Epub 2014 Jun 12.
Interferon γ (IFN-γ), an anticancer agent, is a strong inducer of indoleamine 2,3-dioxygenase 1 (IDO1), which is a tryptophan-metabolizing enzyme involved in the induction of tumor immune tolerance. In this study, we investigated the IDO1 expression in organs after IFN-γ gene transfer to mice. IFN-γ gene transfer greatly increased the mRNA expression of IDO1 in many tissues with the highest in the liver. This upregulation was associated with reduced L-tryptophan levels and increased L-kynurenine levels in serum, indicating that IFN-γ gene transfer increased the IDO activity. Then, Lewis lung carcinoma (LLC) tumor-bearing wild-type and IDO1-knockout (IDO1 KO) mice were used to investigate the effects of IDO1 on the antitumor activity of IFN-γ. IFN-γ gene transfer significantly retarded the tumor growth in both strains without any significant difference in tumor size between the two groups. By contrast, the IDO1 activity was increased only in the wild-type mice by IFN-γ gene transfer, suggesting that cells other than LLC cells, such as tumor stromal cells, are the major contributors of IDO1 expression in LLC tumor. Taken together, these results imply that IFN-γ gene transfer mediated IDO1 upregulation in cells other than LLC cells has hardly any effect on the antitumor activity of IFN-γ.
干扰素γ（IFN-γ）作为一种抗癌药物，是吲哚胺2,3-双加氧酶1（IDO1）的强效诱导剂，IDO1是一种参与诱导肿瘤免疫耐受的色氨酸代谢酶。在本研究中，我们调查了向小鼠进行IFN-γ基因转移后各器官中IDO1的表达情况。IFN-γ基因转移极大地增加了许多组织中IDO1的mRNA表达，其中肝脏中的表达最高。这种上调与血清中L-色氨酸水平降低和L-犬尿氨酸水平升高有关，表明IFN-γ基因转移增加了IDO活性。然后，利用携带Lewis肺癌（LLC）的野生型和IDO1基因敲除（IDO1 KO）小鼠来研究IDO1对IFN-γ抗肿瘤活性的影响。IFN-γ基因转移显著抑制了两种品系小鼠的肿瘤生长，两组之间肿瘤大小无显著差异。相比之下，IFN-γ基因转移仅使野生型小鼠的IDO1活性增加，这表明除LLC细胞外的其他细胞，如肿瘤基质细胞，是LLC肿瘤中IDO1表达的主要贡献者。综上所述，这些结果表明，IFN-γ基因转移介导的LLC细胞以外的细胞中IDO1上调对IFN-γ的抗肿瘤活性几乎没有影响。
