title: Downregulation of the AU-rich RNA-binding protein ZFP36 in chronic HBV patients: implications for anti-inflammatory therapy.
abstract: Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4(+) and CD8(+) T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14(+) monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection.
authors.affiliation: Key Laboratory of Systems Biology of Pathogens, Ministry of Health, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Dongcheng District, Beijing, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Jin
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Chen
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liao
authors.forename: Lu-Lu
authors.initials: LL
authors.lastname: Gong
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Yuan
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Zhao
authors.forename: Ding
authors.initials: D
authors.lastname: Zhang
authors.forename: Xia
authors.initials: X
authors.lastname: Feng
authors.forename: Jing-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Chen
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Yan
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000494:pharmacology; D002681:China; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D055785:Gene Knockdown Techniques; D006509:Hepatitis B / Q000150:complications / Q000378:metabolism*; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D016209:Interleukin-8 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D016207:Cytokines; D017931:DNA Primers; D006514:Hepatitis B Surface Antigens; D016209:Interleukin-8; D034741:RNA, Small Interfering; D051816:Tristetraprolin; C497552:ZFP36 protein, human