title: Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-kappaB and increases migration of leukocytes.
abstract: Interferon-gamma inducible protein 10 (IP-10) involves inflammatory cell recruitment and cellular immune damage during virus infection. Although an increase of the peripheral IP-10 level is known in HBV-infected patients, the molecular basis of HBV infection inducing IP-10 expression has remained elusive. In the present study, we demonstrate that hepatitis B virus protein X (HBx) increases IP-10 expression in a dose-dependent manner. Transfection of the HBx-expressing vector into HepG2 cells results in nuclear translocation of NF-kappaB, which directly binds the promoter of IP-10 at positions from -122 to -113, thus facilitating transcription. The addition of the NF-kappaB inhibitor blocks the effect of HBx on IP-10 induction. In parallel, increase of NF-kappaB subunits p65 and p50 in HepG2 cells also augments IP-10 expression. Furthermore, we show that HBx induces activation of NF-kappaB through the TRAF2/TAK1 signaling pathway, leading to up-regulation of IP-10 expression. As a consequence, up-regulation of IP-10 may mediate the migration of peripheral blood leukocytes in a NF-kappaB-dependent manner. In conclusion, we report a novel molecular mechanism of HBV infection inducing IP-10 expression, which involves viral protein HBx affecting NF-kappaB pathway, leading to transactivation of the IP-10 promoter. Our study provides insight into the migration of leukocytes in response to HBV infection, thus causing immune pathological injury of liver.
authors.affiliation: Departments of Immunology, Tongji Medical College, Huazhong University of Science and Technology,Wuhan 430030, Hubei Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Ma
authors.forename: Zhang
authors.initials: Z
authors.lastname: Lei
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Zhu
authors.forename: Ping
authors.initials: P
authors.lastname: Lei
authors.forename: Zhuo-Shun
authors.initials: ZS
authors.lastname: Yang
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Yao
authors.forename: Chuan
authors.initials: C
authors.lastname: Shi
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Sun
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Wu
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.forename: Guan-Xin
authors.initials: GX
authors.lastname: Shen
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
mesh_terms: D020121:5' Untranslated Regions; D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D020121:5' Untranslated Regions; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D017931:DNA Primers; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein