title: Hepatitis B virus induces IL-23 production in antigen presenting cells and causes liver damage via the IL-23/IL-17 axis.
abstract: IL-23 regulates myriad processes in the innate and adaptive immune systems, and is a critical mediator of the proinflammatory effects exerted by Th17 cells in many diseases. In this study, we investigated whether and how hepatitis B virus (HBV) causes liver damage directly through the IL-23 signaling pathway. In biopsied liver tissues from HBV-infected patients, expression of both IL-23 and IL-23R was remarkably elevated. In vivo observations also indicated that the main sources of IL-23 were myeloid dendritic cells (mDCs) and macrophages. Analysis of in vitro differentiated immature DCs and macrophages isolated from healthy donors revealed that the HBV surface antigen (HBsAg) efficiently induces IL-23 secretion in a mannose receptor (MR)-dependent manner. Culture with an endosomal acidification inhibitor and the dynamin inhibitor showed that, upon binding to the MR, the HBsAg is taken up by mDCs and macrophages through an endocytosis mechanism. In contrast, although the HBV core antigen (HBcAg) can also stimulate IL-23 secretion from mDCs, the process was MR- and endocytosis-independent. In addition, IL-23 was shown to be indispensible for HBsAg-stimulated differentiation of naïve CD4(+) T cells into Th17 cells, which were determined to be the primary source of IL-17 in HBV-infected livers. The cognate receptor, IL-17R, was found to exist on the hepatic stellate cells and mDCs, both of which might represent the potential target cells of IL-17 in hepatitis B disease. These data provide novel insights into a yet unrecognized mechanism of HBV-induced hepatitis, by which increases in IL-23 expression, through an MR/endocytosis-dependent or -independent manner, produce liver damage through the IL-23/IL-17 axis.
authors.affiliation: Institute of Immunology, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jijun
authors.initials: J
authors.lastname: Zhou
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Tian
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zemin
authors.initials: Z
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Tian
authors.forename: Zhengcai
authors.initials: Z
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: van Velkinburgh
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Bian
authors.forename: Yifang
authors.initials: Y
authors.lastname: Ping
authors.forename: Bing
authors.initials: B
authors.lastname: Ni
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006509:Hepatitis B / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism; D006515:Hepatitis B virus / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053722:Receptors, Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D006514:Hepatitis B Surface Antigens; C109985:IL17RA protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D053722:Receptors, Interleukin-17