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      Hepatitis B Virus Induces IL-23 Production in Antigen Presenting Cells and Causes Liver Damage via the IL-23/IL-17 Axis

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          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.

          Author Summary

          While it is known that IL-23 plays a pivotal role in maintenance of the Th17 phenotype and their production of the IL-17 cytokine, the mechanisms by which HBV induces particular immune cell types to produce IL-23 remain unknown. In the study of human hepatitis B described herein, we demonstrated that IL-23 is principally derived from the liver myeloid dendritic cells (mDCs) and macrophages. In vitro assay showed that mDCs produce large amounts of IL-23 upon stimulation with HBV surface antigen (HBsAg) through the mannose receptor (MR) and an endocytosis mechanism. In contrast, although the HBV core antigen (HBcAg) was also capable of stimulating IL-23 secretion from mDCs, the process occurs in an MR- and endocytosis-independent manner. IL-23 was also shown to efficiently stimulate the differentiation of naïve CD4 + T cells into Th17 cells in the presence of HBsAg or HBcAg; furthermore, the Th17 cells were shown to be the primary source of IL-17. The results also indicated that both hepatic satellite cells and mDCs might be the potential target cells of IL-17 in hepatitis B disease. Therefore, our study not only provides further insights into the mechanisms underlying HBV pathogenesis, but also suggests the potential intervening targets for patient treatment.

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          Most cited references43

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          Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.

          Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
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            Increased expression of interleukin 17 in inflammatory bowel disease.

            Interleukin (IL) 17 is a cytokine which exerts strong proinflammatory activities. In this study we evaluated changes in IL-17 expression in the inflamed mucosa and in the serum of patients with inflammatory bowel disease (IBD). Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n=20), Crohn's disease (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal colorectal tissues (n=15). IL-17 expression was evaluated by a standard immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17 mRNA expression was analysed by reverse transcriptase-polymerase chain reaction. IL-17 expression was not detected in samples from normal colonic mucosa, infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and CD patients, IL-17 expression was clearly detectable in CD3(+) T cells or CD68(+) monocytes/macrophages. The average number of IL-17(+) cells was significantly increased in active UC and CD patients compared with inactive patients. IL-17 mRNA expression was not detected in normal mucosa but was detectable in the mucosa from active UC and CD patients. IL-17 was not detected in the sera from normal individuals, infectious colitis, or ischaemic colitis patients but IL-17 levels were significantly elevated in IBD patients. IL-17 expression in the mucosa and serum was increased in IBD patients. It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa.
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              The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.

              Interleukin 23 (IL-23) is required for autoimmune inflammation mediated by IL-17-producing helper T cells (T(H)-17 cells) and has been linked to many human immune disorders. Here we restricted deficiency in the IL-23 receptor to defined cell populations in vivo to investigate the requirement for IL-23 signaling in the development and function of T(H)-17 cells in autoimmunity, inflammation and infection. In the absence of IL-23, T(H)-17 development was stalled at the early activation stage. T(H)-17 cells failed to downregulate IL-2 and also failed to maintain IL-17 production or upregulate expression of the IL-7 receptor alpha-chain. These defects were associated with less proliferation; consequently, fewer effector T(H)-17 cells were produced in the lymph nodes and hence available to emigrate to the bloodstream and tissues.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2013
                June 2013
                27 June 2013
                : 9
                : 6
                : e1003410
                Affiliations
                [1 ]Institute of Immunology, Third Military Medical University, Chongqing, People′s Republic of China
                [2 ]Ministry of Education Key Laboratory of Child Development and Disorders, Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, People′s Republic of China
                [3 ]Department of Infectious Diseases, Southwestern Hospital, Third Military Medical University, Chongqing, People′s Republic of China
                [4 ]Department of Immunology, Medical College of Qingdao University, Qingdao, People′s Republic of China
                [5 ]van Velkinburgh Initiative for Collaboratory Biomedical Research, Santa Fe, New Mexico, United States of America
                [6 ]Department of Pathology, Southwestern Hospital, Third Military Medical University, Chongqing, People′s Republic of China
                University of California, San Diego, United States of America
                Author notes

                The authors have no conflict of interests to declare.

                Conceived and designed the experiments: Y. Wu, B. Ni. Performed the experiments: Q. Wang, J. Zhou, B. Zhang, Y. Tian, Z. Tian, Z. Jia, J. Tang, Y. Tang, Z. Huang, X. Bian, Y. Ping. Analyzed the data: Y. Zheng. Contributed reagents/materials/analysis tools: Q. Mao. Wrote the paper: J. Velkinburgh.

                Article
                PPATHOGENS-D-12-02109
                10.1371/journal.ppat.1003410
                3694858
                23825942
                c8b78367-7e4b-472f-a2de-c8499c8a8c57
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 August 2012
                : 25 April 2013
                Page count
                Pages: 15
                Funding
                This work was funded by grants from the Major State Basic Research Development Program of China (973 Program) (Nos. 2007CB512401 and 2007CB512805, http://program.most.gov.cn/), the Major Program of National Natural Science Foundation of China (No. 30930086, http://www.nsfc.gov.cn/Portal0/default152.htm), the General Program of National Natural Science Foundation of China (No. 31070798, http://www.nsfc.gov.cn/Portal0/default152.htm), and the National Major Project for New Drug Creation (No. 2009ZX09503-005, http://program.most.gov.cn/#). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Infectious Diseases
                Viral Diseases
                Hepatitis
                Hepatitis B
                Gastrointestinal Infections

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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