title: Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection.
abstract: Clearance of hepatitis B virus infection (HBV) infection implies a polyclonal vigorous T-helper 1 (Th1) and cytotoxic T-lymphocyte (CTL) response. Interleukin-18 (IL-18), a monokine that shares functional abilities with IL-12, is a potent inductor of interferon-gamma (IFN-gamma) by Th1 and natural killer (NK) cells. However, the role and regulation in HBV infection of IFN-gamma have not been defined. This study therefore sought to determine hepatitis B core antigen (HBcAg)-mediated regulation of IL-18 production in peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and patients with chronic hepatitis B (CHB) or acute hepatitis B (AHB); 31 HC, 27 patients with CHB and 8 patients with AHB infection were included in the study. HBcAg-mediated induction of IL-18 was determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and specific enzyme-linked immunosorbent assay (ELISA). HBcAg induced IL-18 gene transcription and dose-dependent secretion of mature IL-18 protein in HC, CHB, and AHB. HBcAg-dependent IL-18 levels were abrogated by inhibition of Caspase-1, but not by blockade of CD40-CD154 interaction. Serum levels of IFN-gamma correlated inversely with viremia in patients with CHB (rho = - 0.54, P < 0.05), but not with serum levels of IL-12 or IL-18. Interestingly, in PBMCs of HBeAg-negative patients, HBcAg induced significantly higher amounts of IL-18 than in those of HBeAg-positive patients. A variant, lacking the histone-like arginine-rich domain, did not induce IL-18 in either HC or CHB in vitro. Taken together, these results indicate that HBcAg induces IL-18 secretion by induction of Caspase-1. Differential regulation in HBeAg-negative and positive patients suggests an important role of IL-18 in CHB infection.
authors.affiliation: Department of Medicine II, Gastroenterology/Hepatology/Infectious Diseases, University Hospital Mannheim, Mannheim, Germany. manigold@nih.gov
authors.forename: Tobias
authors.initials: T
authors.lastname: Manigold
authors.forename: Ulrich
authors.initials: U
authors.lastname: Böcker
authors.forename: Jingsan
authors.initials: J
authors.lastname: Chen
authors.forename: Jutta
authors.initials: J
authors.lastname: Gundt
authors.forename: Petra
authors.initials: P
authors.lastname: Traber
authors.forename: Manfred V
authors.initials: MV
authors.lastname: Singer
authors.forename: Siegbert
authors.initials: S
authors.lastname: Rossol
mesh_terms: D000328:Adult; D005260:Female; D005786:Gene Expression Regulation; D006509:Hepatitis B / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014158:Transcription, Genetic
chemical_list: D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma