title: Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein.
abstract: Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed in vitro using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-alpha) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-alpha production.
  
  
  CONCLUSIONS
  This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response.
authors.affiliation: Murdoch Children's Research Institute, Melbourne, Australia. kumar.visvanathan@med.monash.edu.au
authors.forename: Kumar
authors.initials: K
authors.lastname: Visvanathan
authors.forename: Narelle A
authors.initials: NA
authors.lastname: Skinner
authors.forename: Alex J V
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Riordan
authors.forename: Vitini
authors.initials: V
authors.lastname: Sozzi
authors.forename: Roslyn
authors.initials: R
authors.lastname: Edwards
authors.forename: Sally
authors.initials: S
authors.lastname: Rodgers
authors.forename: Jelica
authors.initials: J
authors.lastname: Kurtovic
authors.forename: Judy
authors.initials: J
authors.lastname: Chang
authors.forename: Sharon
authors.initials: S
authors.lastname: Lewin
authors.forename: Paul
authors.initials: P
authors.lastname: Desmond
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006512:Hepatitis B Core Antigens / Q000097:blood / Q000502:physiology; D006513:Hepatitis B e Antigens / Q000097:blood / Q000502:physiology; D006515:Hepatitis B virus / Q000276:immunology / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014758:Viral Core Proteins / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology
chemical_list: D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins