Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein.
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.
Visvanathan
Kumar
K
Murdoch Children's Research Institute, Melbourne, Australia. kumar.visvanathan@med.monash.edu.au
Skinner
Narelle A
NA
Thompson
Alex J V
AJ
Riordan
Stephen M
SM
Sozzi
Vitini
V
Edwards
Roslyn
R
Rodgers
Sally
S
Kurtovic
Jelica
J
Chang
Judy
J
Lewin
Sharon
S
Desmond
Paul
P
Locarnini
Stephen
S
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
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