Upregulation of IL-23 Expression in Patients with Chronic Hepatitis B Is Mediated by the HBx/ERK/NF-κB Pathway
Upregulation of IL-23 Expression in Patients with Chronic Hepatitis B Is Mediated by the HBx/ERK/NF-κB Pathway
复制标题
慢性乙型肝炎患者IL-23表达的上调是由HBx/ERK/NF-κB通路介导的
DOI：
10.4049/jimmunol.1101652
复制
发表时间：
2012-01-15
影响因子：
4.4
通讯作者：
Wu, Kaichun
中科院分区：
文献类型：
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作者：
Xia, Limin;Tian, Dean;Wu, Kaichun
IL-23是一种新发现的促炎细胞因子，有助于维持和扩增Th 17细胞。IL-23最近被确定为在许多慢性炎性疾病中起关键作用。然而，IL-23在慢性B型肝炎（CH B）中的调节机制仍不清楚。本研究旨在检测IL-23在慢性B型肝炎患者中的表达，探讨B型肝炎病毒（HBV）诱导IL-23表达的分子机制。CHB患者血清IL-23水平和肝脏表达显着上调。IL-23表达与组织学活动指数评分、HBV DNA载量、血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平呈正相关。HBx蛋白以剂量依赖性方式增加IL-23表达。它还有助于NF-κB的核转位，NF-κ B直接与IL-23亚基p19和p40的启动子结合，以促进其转录。NF-κB抑制剂阻断HBx诱导IL-23表达的作用，NF-κB亚单位p65和p50增加IL-23表达。抑制ERK 1/2活化和转染ERK显性负性质粒可显著阻断HBx诱导的IL-23表达。此外，PI 3 K和Ras-MEK-MAPK抑制剂显著降低ERK 1/2活化和IL-23表达。因此，我们报道了HBV诱导IL-23表达的一种新的分子机制，它涉及HBx激活ERK/NF-κB通路，导致IL-23 p19和p40启动子的反式激活。
IL-23 is a newly discovered proinflammatory cytokine that contributes to the maintenance and expansion of Th17 cells. IL-23 has recently been identified as playing a critical role in a number of chronic inflammatory diseases. However, the regulatory mechanism of IL-23 in chronic hepatitis B (CHB) remains largely unknown. The aims of this study were to detect the expression of IL-23 in CHB patients and to explore the molecular mechanism of hepatitis B virus (HBV)-induced IL-23 expression. Serum levels and hepatic expression of IL-23 were significantly upregulated in CHB patients. A positive correlation was found between IL-23 expression and the histological activity index score, HBV DNA load, and serum alanine aminotransferase and aspartate aminotransferase levels. HBx protein increased IL-23 expression in a dose-dependent manner. It also aided in the nuclear translocation of NF-κB, which directly bound to the promoters of IL-23 subunits p19 and p40 to facilitate their transcription. NF-κB inhibitors blocked the effect of HBx on IL-23 induction, and NF-κB subunits p65 and p50 increased the augmented IL-23 expression. Inhibition of ERK1/2 activation and transfection with ERK dominant-negative plasmid significantly blocked the HBx-induced IL-23 expression. Furthermore, PI3K and Ras–MEK–MAPK inhibitors significantly decreased the ERK1/2 activation and IL-23 expression. Thus, we report a new molecular mechanism for HBV-induced IL-23 expression, which involves the activation of the ERK/NF-κB pathway by HBx, leading to the transactivation of the IL-23 p19 and p40 promoters.