title: Upregulation of IL-23 expression in patients with chronic hepatitis B is mediated by the HBx/ERK/NF-κB pathway.
abstract: 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.
authors.affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China.
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.forename: Dean
authors.initials: D
authors.lastname: Tian
authors.forename: Wenjie
authors.initials: W
authors.lastname: Huang
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors / Q000235:genetics; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D053760:Interleukin-23 Subunit p19 / Q000037:antagonists & inhibitors / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein