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 HBeAgnegative 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-β£) 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-β£ production. Conclusion: This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response. (HEPATOLOGY 2007;45: 102-110.) H epatitis B virus can cause acute and chronic infection and is one of the major causes of hepatocellular carcinoma (HCC). 1,2 The DNA genome of HBV contains four open reading frames, and expression of one of these, the pre C-C gene, is one of several strategies used by HBV to ensure persistence in the infected individual. 3 Hepatitis B e antigen (HBeAg) is the major product of the pre C-C gene 3 and is a secreted, nonparticulate form of the viral nucleocapsid. 3,4 The HBeAg is regarded as an accessory protein of HBV and is not required for viral replication or infection. The natural history of chronic hepatitis B (CHB) typically is divided into two phases: HBeAg-positive and HBeAg-negative.
Appropriate sensing and recognition of invasive microbes is an essential first task of the immune response. Detection of these pathogens is mainly carried out by the use of a variety of pattern recognition receptors, including Toll like receptors (TLR). Although most interest has focused on bacterial detection, viruses also can be detected by this system, as in the example of TLR3 being activated in response to viral double-stranded RNA (dsRNA) . [5][6][7] Recent studies suggest that some viruses may suppress host defense by disabling aspects of the TLR mechanism, providing evidence for the importance of innate immunity in the antiviral response. [8][9][10] The receptors of the innate immune system, including the TLRs, are encoded in the germ line and differ from antigen receptors in a number of ways. They are expressed on many different antigen-presenting cells, including