J Immunol 2011 Nov;187 (9): 4844-60. [IF:5.745]
Hepatitis B Virus Induces a Novel Inflammation Network Involving Three Inflammatory Factors, IL-29, IL-8, and Cyclooxygenase-2.
Yu Y , Gong R , Mu Y , Chen Y , Zhu C , Sun Z , Chen M , Liu Y , Zhu Y , Wu J .
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China;
湖北武汉大学生命科学学院，病毒学国家重点实验室
Abstract
Chronic inflammation induced by hepatitis B virus (HBV) is a major causative factor associated with the development of cirrhosis and hepatocellular carcinoma. In this study, we investigated the roles of three inflammatory factors, IL-8, IL-29 (or IFN-λ1), and cyclooxygenase-2 (COX-2), in HBV infection. We showed that the expression of IL-29, IL-8, and COX-2 genes was enhanced in HBV-infected patients or in HBV-expressing cells. In HBV-transfected human lymphocytes and hepatocytes, IL-29 activates the production of IL-8, which in turn enhances the expression of COX-2. In addition, COX-2 decreases the production of IL-8, which in turn attenuates the expression of IL-29. Thus, we proposed that HBV infection induces a novel inflammation cytokine network involving three inflammatory factors that regulate each other in the order IL-29/IL-8/COX-2, which involves positive regulation and negative feedback. In addition, we also demonstrated that COX-2 expression activated by IL-8 was mediated through CREB and C/EBP, which maintains the inflammatory environment associated with HBV infection. Finally, we showed that the ERK and the JNK signaling pathways were cooperatively involved in the regulation of COX-2. We also demonstrated that IL-29 inhibits HBV replication and that IL-8 attenuates the expression of IL-10R2 and the anti-HBV activity of IL-29, which favors the establishment of persistent viral infection. These new findings provide insights for our understanding of the mechanism by which inflammatory factors regulate each other in response to HBV infection.
摘要
乙型肝炎病毒HBV引起的慢性乙型肝炎是肝硬化和肝癌相关的危险因素。该研究中，我们研究了3个炎症因子IL-8、IL-29和环氧化酶2(COX2)，在HBV感染后发挥的作用。我们发现在HBV感染的病人或表达HBV的细胞中，这三个基因的表达都上调。在转染了HBV的人淋巴细胞和肝细胞中，IL-29诱导IL-8的表达，而IL-8可以上调COX-2的表达。此外，COX-2可以下调IL-8，亦降低IL-29表达。因此我们提出HBV感染后可诱导产生一个新的炎症因子网络--可以相互调节、既有正反馈也有负反馈的IL-29/IL-8/COX-2。此外，我们还发现IL-8上调COX-2的表达是通过CREB和C/EBP介导的，而CREB和C/EBP可维持HBV感染后的炎症环境。最后，我们还发现ERK和JNK的信号通路也参与调节了COX-2的表达。我们还发现IL-29可抑制HBV的复制，而IL-8可下调IL-10R2的表达并削弱IL-29的抗HBV能力，这可导致HBV的持续性感染。这些新的发现为我们了解HBV感染后炎症因子的相互调节提供了新的思路。
