The host genetic factors involving genetic polymorphisms are believed to be responsible for clinical outcomes of infectious disease[9, 17, 19], because differences in the susceptibility to infection or severity of disease cannot solely be attributed to the virulence of an organism. For chronic viral hepatitis, genetic associations are likely to provide some clues to viral persistence and disease progression, and might lead to a new therapeutic approach. Recent studies have shown that several immunoregulatory cytokines such as IFN-γand TNF-α inhibit HBV replication through the noncytolytic process. In contrast, IL-10 counteracts their effector mechanisms[8, 10, 11, 17]. Because the capacity for cytokine production in individuals largely depends on genetic polymorphisms, heterogeneity of the candidate gene in patients with HBV emerges as a probable biomarker for determining the disease phenotypes.
In HCV infection, the influence of IL-10 genotypes either on different clinical features of liver disease or in the response to antiviral therapy has been evaluated in several studies: data are highly controversial with some studies showing a positive association and others denying such a link[18, 22, 23]. Taken together, the some investigation has shown that responsiveness to IFN-αtreatment in patients with chronic hepatitis C is closely linked to ATA haplotype of the IL-10 gene promoter. For example Edwards-Smith et al. showed an association of the IL-10 (-592) CC genotype with NR and ATA haplotype with SR. Although IL-10 has both anti-inflammatory and antifibrotic properties, high levels of IL-10 production may increase viral replication in chronic HBV infection and result in influence of the immune response, moreover, there are differences in the immunopathogenesis of HBV and HCV infection. So the association between IL-10 promoter polymorphism and the response to IFN-αtherapy in HBV infection may be evaluated.
In our study, when comparing HBV-infected patients with healthy volunteers, no different distribution of the three cytokine genotypes was observed. It demonstrates the patients and healthy controls share an identical genetic background and the cytokine polymorphisms do not influence susceptibility to the HBV infection.
Our results also indicate that inheritance of particular IL-10 promoter genotypes/haplotypes has a significant role in determining the initial response of HBV infection to treatment with IFN-α. Inheritance of the -592A and -819T alleles, along with the exclusively linked -592A/A and -819T/T genotypes or the ATA haplotype (lower IL-10 producer) were significantly associated with "responder" status. Two sites are dimorphic, and reciprocal effects (nonresponse) were also seen with the -592C and -819C alleles. Homozygosity for genotypes -592A/A and -819T/T was more strongly associated with sustained response than heterozygosity.
As a potent immune modulator, IL-10 may exert a profound impact on the overall therapeutic outcome in patients with HBV. High serum levels of IL-10 have been correlated with poor response to interferon therapy, whereas IL-10 production has been found to be lower in responders than in nonresponders[14, 19]. Both CD4+ T-helper cell and CD8+ cytotoxic T-lymphocyte (CTL) responses are important in HBV infection. If IL-10 operates through T-lymphocyte pathways, the exact mechanism of action may be complicated. IL-10 may down-regulate MHC class I and class II expression, impeding both CTL and antibody responses, but may enhance natural killer cell activity[24, 25]. Strong anti-HBV-specific T-helper response may contribute to self-limiting HBV infection and sustained response to interferon therapy, and similar effects can be attributed to HBV-specific CTL response [26, 27].
The mechanism of IL-10 Promoter Polymorphism and the HBV infection sustained response to interferon therapy need to further study. If serum IL-10 were detected in the SR and NR, this study would give more evidence. It may be interesting to investigate the promoter of IL-10 polymorphisms and HBV patients initial response of chronic hepatitis B to IFN-α therapy in Caucasians patients.
In summary, Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of HBV infection to IFN-α therapy. Patients who are genetically predisposed to high IL-10 production have a poor response to IFN-α and may benefit from additional treatment strategies designed to enhance a Th1 response in the meantime. Identifying other predictors, especially host genetic factors, for treatment outcome in these patients may help in making appropriate treatment decisions.