Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.
Hepatology. 2014 Mar;59(3):828-38. doi: 10.1002/hep.26788. Epub 2014 Jan 27.
Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-λ4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1.
Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype.
与治疗敏感的 IL28B 主要基因型（MA；rs8099917 处 TT）相比，预处理时肝干扰素（IFN）刺激基因（ISG）的上调与治疗抵抗的 IL28B 次要基因型（MI；rs8099917 处 TG/GG）具有更强的相关性。我们比较了 146 例接受聚乙二醇干扰素和利巴韦林联合治疗的慢性丙型肝炎患者肝和血液中的 ISG 表达。使用 Affymetrix GeneChip（Affymetrix，Santa Clara，CA）分析了 85 例患者的肝和血液基因表达谱。MA 患者的 MA 患者肝和血液中的 ISG 表达相关，而 MI 患者则无相关性。这种相关性的丧失是由于 MI 患者的免疫细胞无法渗透到肝小叶中所致，这通过使用激光捕获微切割和免疫组织化学染色对肝小叶和门脉区进行区域基因表达分析得到了证实。尽管 MI 患者的免疫细胞水平较低，但肝 ISG 在 MI 患者的肝中仍被上调，并且发现它们受到多种因素的调节，即 IL28A/B、IFN-λ4 和无翅相关的 MMTV 整合位点 5A（WNT5A）。有趣的是，WNT5A 通过诱导应激颗粒蛋白 GTP 酶激活蛋白（SH3 结构域）结合蛋白 1（G3BP1）的表达，诱导 ISG 的表达，同时也增加了丙型肝炎病毒的复制，在 Huh-7 细胞系中。在肝脏中，WNT5A 及其受体 frizzled 家族受体 5 的表达与 G3BP1 显著相关。
IL28B 次要基因型患者的肝脏中失去了免疫细胞，并诱导了其他炎症介质，如 WNT5A 的表达。这可能与这些患者肝 ISG 表达水平高和 IL28B 次要基因型的治疗抵抗表型有关。
