Interleukin 18 promoter variants (-137G>C and -607C>A) in patients with chronic hepatitis C: association with treatment response.

BACKGROUND: Recently, two functional IL18 promoter variants, -607C>A (rs1946518) and -137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response. METHODS: Seven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%. RESULTS: Genotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the -607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072-2.205) and the -137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040-2.233). CONCLUSIONS: The association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.

Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis.

OBJECTIVE: Toll-like receptors (TLR) 2 and 4 were shown recently to mediate lipopolysaccharide (LPS)/endotoxin effects in vivo. Absence of clinical features, such as fever and leucocytosis, frequent infections, and up-regulation of anti-inflammatory cytokines suggest systemic differential regulation of LPS effects in patients with chronic endotoxinaemia due to liver cirrhosis. DESIGN: Regulation of TLR2 and TLR4 represents a possible pathway to control LPS-induced immune responses in liver cirrhosis. METHODS: We compared the expression of TLR2 and TLR4 in peripheral blood mononuclear cells (PBMC) (n = 28) and in liver biopsies (n = 20) of controls and of patients with liver cirrhosis by applying the reverse transcriptase polymerase chain reaction technique. The data were correlated to serum levels of LPS and CD14. RESULTS: Expression of TLR2 was up-regulated (P < 0.01 to P < 0.05) in the PBMC of patients with high serum endotoxin levels, while TLR4 expression in patients at Child-Pugh stage A was down-regulated, irrespective of the origin (alcoholic or viral) of cirrhosis. A strong and significant correlation between expression of TLR2 and serum LPS (r = 0.638, P < 0.01) and soluble CD14 (r = 0.550, P < 0.05) was observed. Intrahepatic expression of TLR2/4 was not altered significantly in patients with liver cirrhosis. CONCLUSION: Our data indicate LPS-driven regulation of TLR2/4 in patients with liver cirrhosis, suggesting involvement in mechanisms of systemic LPS hyporesponsiveness.

Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection.

Clearance of hepatitis B virus infection (HBV) infection implies a polyclonal vigorous T-helper 1 (Th1) and cytotoxic T-lymphocyte (CTL) response. Interleukin-18 (IL-18), a monokine that shares functional abilities with IL-12, is a potent inductor of interferon-gamma (IFN-gamma) by Th1 and natural killer (NK) cells. However, the role and regulation in HBV infection of IFN-gamma have not been defined. This study therefore sought to determine hepatitis B core antigen (HBcAg)-mediated regulation of IL-18 production in peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and patients with chronic hepatitis B (CHB) or acute hepatitis B (AHB); 31 HC, 27 patients with CHB and 8 patients with AHB infection were included in the study. HBcAg-mediated induction of IL-18 was determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and specific enzyme-linked immunosorbent assay (ELISA). HBcAg induced IL-18 gene transcription and dose-dependent secretion of mature IL-18 protein in HC, CHB, and AHB. HBcAg-dependent IL-18 levels were abrogated by inhibition of Caspase-1, but not by blockade of CD40-CD154 interaction. Serum levels of IFN-gamma correlated inversely with viremia in patients with CHB (rho = - 0.54, P < 0.05), but not with serum levels of IL-12 or IL-18. Interestingly, in PBMCs of HBeAg-negative patients, HBcAg induced significantly higher amounts of IL-18 than in those of HBeAg-positive patients. A variant, lacking the histone-like arginine-rich domain, did not induce IL-18 in either HC or CHB in vitro. Taken together, these results indicate that HBcAg induces IL-18 secretion by induction of Caspase-1. Differential regulation in HBeAg-negative and positive patients suggests an important role of IL-18 in CHB infection.