There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS).
The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable severity of HCV recurrence.
The inheritance of polymorphisms in TGF-beta1, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and genes of the renin-angiotensin system was examined in 128 patients with chronic HCV.
Thirty Caucasians with cirrhosis due to chronic HCV infection and 114 HCV-infected patients histopathologically free of cirrhosis were genotyped for genetic variants in TNF, lymphotoxin alpha and TNF-receptor type I using PCR-based techniques.
Liver TCRgammadelta(+) T-cell lines from HCV-infected individuals had high levels of non-major histocompatibility complex (MHC)-restricted cytotoxic activity against different targets including primary hepatocytes and produced interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 8 (IL-8) following activation by anti-CD3.
Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders.
We measured the transaminases levels, the liver disease grading and staging scores, the intrahepatic interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-4 and IL-10 mRNA levels, the serum and liver hepatitis C virus (HCV) RNA titers, and the intrahepatic HCV envelope 2 protein staining score before and after 12 weeks of ribavirin monotherapy.
Our aims were: (i) to characterize serum levels of tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in non-cirrhotics with hepatitis C; (ii) to correlate levels of theses cytokines with degree of disease at baseline; (iii) to characterize the immunomodulatory effects of therapy with response and (iv) to compare profiles of cytokines in patients treated with pegylated-interferon alpha-2b monotherapy (PMT) vs its combination with ribavirin (PCT1-low dose ribavirin and PCT2-high dose ribavirin).
To explore whether a correlation exists between these two factors, we measured pretreatment gammaGT levels in serum and TNF-alpha mRNA levels in liver biopsies of chronic HCV patients.
Although previous work has suggested potential roles for TNF in the pathogenesis of HCV infection, we were unable to identify any link between TNF genetic polymorphisms and histological severity or response to antiviral therapy.
We have previously reported that the HCV NS5A protein interacts with tumor necrosis factor (TNF) receptor-associated factor (TRAF) domain of TRAF2 (Park, K.-J., Choi, S.-H., Lee, S. Y., Hwang, S. B., and Lai, M. M. C. (2002) J. Biol.Chem.277, 13122-13128).
The evaluation of combined TNF-alpha and IL-10 genotypes revealed a significant increase of the "anti-inflammatory genotype" (low-TNF/high-IL-10 producers) in resolved HCV infection group compared with patients with persistent HCV infection.
In conclusion, our findings suggest that -308 TNF-alpha promoter polymorphisms do not play a direct role in the susceptibility and pathogenesis of HCV infection, and in the response to interferon-alpha therapy for CHC.
Genetic polymorphisms in proinflammatory cytokines, the interleukin 1 (IL-1) family (IL-1beta and IL-1ra) and tumor necrosis factor-alpha (TNF-alpha), were studied in 274 Japanese patients with chronic HCV infection and 55 healthy individuals using standard polymerase chain reaction-based genotyping techniques.
The promoter polymorphism of the TNF-alpha gene investigated herein is equally distributed in healthy individuals and patients with hepatitis C and does not seem to predict the response to therapy with interferon alfa-2a and ribavirin.
The evaluation of combined TNF-alpha and IL-10 genotypes revealed a significant increase of the "anti-inflammatory genotype" (low-TNF/high-IL-10 producers) in resolved HCV infection group compared with patients with persistent HCV infection.
As compared with controls, we found major changes in T-lymphocyte subsets in HCV-infected patients, with a significant decrease of T-cell antigen receptor (TCR) delta and CD56 gene expression, associated with a concomitant increase of TCRalpha and CD8beta that were correlated with cytotoxic factors, proinflammatory chemokines, and chemokine receptors including peforin, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, and CXCR3.
Increased expression of TNF-alpha may be involved in the pathogenesis of liver injury and progression of fibrosis in individuals who have steatosis in association with chronic HCV.
HCV replication was also found to modulate I-TAC expression, with stimulation of Huh-7 cells harboring either the HCV subgenomic or genomic replicon showing significantly increased synergistic effects compared with those previously seen in Huh-7 cells alone with IFN-gamma and TNF-alpha.