IL-10 and IL-28B gene variants as predictors of sustained response to peginterferon and ribavirin therapy in chronic HCV infection.

OBJECTIVES: Interleukin-10 (IL-10) plays an important role in the immunity to hepatitis C virus (HCV). Insofar as IL-10 variants are associated with altered levels of IL-10, previous studies that examined the association of IL-10 polymorphisms with the susceptibility to and progression of chronic HCV, and response to anti-viral treatment were inconsistent. We investigated the association between common IL-10 variants in the intron and the promotor region with HCV and associated features. METHODS: Study subjects comprised 120 patients infected with HCV-1b, and treated with Peg-IFN/RBV. Genotyping of six IL-10 promoter variants in the intron region (rs1878672, rs1554286, rs1518111) and promotor region (rs1800872, rs1800871, rs1800896) were done by real-time PCR. RESULTS: Compared to G/G, carriage of IL-10 rs1800896 (-1082A/G) A/A genotype was more frequent in patients with sustained virological response (SVR). The decline in viral load over the first 12weeks of treatment was more pronounced in rs1800896 A/A genotype carriers, compared to G/G genotype carriers, and was irrespective of the treatment dosage. Carriage of rs1800896 A/A genotype was positively associated with improvement in viral load decline, which was simultaneous, with and without carriage of the common favourable IL-28B variant. Carriage of both IL-10 rs1800896 G/G and IL-28B non-favourable genotype was associated with twice the risk of getting slow decline of viral load during treatment. Haploview analysis identified ACGCTA and CCGCTG haplotypes to be linked with excellent PegIFN/RBV cure rate, and complete HCV eradication. On the other hand, ACGCTG and CCGCTA haplotypes were associated with resistance to PegIFN/RBV treatment. CONCLUSION: IL-10 rs1800896 variant markedly influences the clinical outcome of HCV infection, and is a determinant of the response to HCV treatment.

Role of TLRs and IL-6 in the outcome of chronic hepatitis C treatment in Tunisian population.

OBJECTIVES: TLRs are one of the most studied families of pathogen recognition receptors (PRRs) and play a pivotal role during HCV infection. The binding of ligands to TLRs on antigen presenting cells (APCs) leads to secretion of inflammatory cytokines, such as IL6, and induction of the acquired immunity response. Therefore, it has become necessarily to harness the TLRs properties' on therapeutically tools to enhance the HCV treatment response. Herein, we investigated the association between TLR3, TLR4 variants and nine IL-6 polymorphisms, and response to anti-viral treatment during HCV infection. METHODS: Study subjects comprised 120 patients infected with HCV-1b and treated with Peg-IFN/RBV. Genotyping of nine IL-6 variants were done by real -time PCR and genotyping of TLRs polymorphisms were done by RFLP-PCR. RESULTS: High frequency of TLR3 rs3775290 C/C genotype and TLR4 rs4986790 A/A genotype were noticed among patients with sustained viral response compared to Non-responder patients. The genetic association of TLR3 and TLR4 variants was evidenced by the improvement in the kinetics of viral load decline, with superiority of TLR3 compared to TLR4. Among, nine polymorphisms studied on IL-6 only rs1800796, rs2069845 and rs1880242 were associated with sustained viral response. Our study reports also that the common favourable IL-28B variant is essential for TLR-activated antiviral protection. CONCLUSION: TLR3 and TLR4 are involved in the pathogenesis of viral infections. TLR3 may be better suited than TLR4 to activate anti-viral program. Moreover, we propose that the Th2 cytokine, IL-6, constitutes a determinant of the outcome of therapy in HCV patients.

Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients.

BACKGROUND: Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear. METHODS: The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR. RESULTS: Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (-819T/C), rs1800872 (-592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment. CONCLUSION: IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC.