640 IN VIVO LIVER ENDOPLASMIC RETICULUM STRESS IN CHRONIC HEPATITIS C

Background: Interleukin 32 (IL-32) is a recently described pro-inflammatory cytokine implicated in chronic hepatitis C virus (HCV)-related inflammation and fibrosis. IL-32α is the most abundant IL-32 isoform. Methods: Circulating IL-32α levels were documented in patients with chronic HCV infections ( n = 31) and compared with individuals who spontaneously resolved HCV infection ( n = 14) and HCV-naive controls ( n = 20). In addition, peripheral blood mononuclear cells (PBMC) from the chronic HCV ( n = 12) and HCV-naive ( n = 9) cohorts were investigated for responses to HCV core and non-structural (NS)3 protein induced IL-32α production. Finally, correlations between IL-32α levels, hepatic fibrosis and subsequent responses to interferon-based therapy were documented in patients with chronic HCV. Results: Circulating IL-32α levels in patients with chronic HCV were similar to those of spontaneously resolved and HCV-naive controls. HCV protein induced IL-32α responses were similar in chronic HCV patients and HCV-naive controls. In patients with chronic HCV, serum IL-32α levels correlated with worsening METAVIR fibrosis (F) scores from F0 to F3 ( r = 0.596, P < 0.001) as did NS3 induced IL-32α responses ( r = 0.837, P < 0.05). However, these correlations were not sustained with the inclusion of IL-32α levels at F4 scores, suggesting events at F4 interfere with IL-32α synthesis or release. In chronic HCV patients who underwent treatment ( n = 28), baseline in vivo and in vitro induced IL-32α concentrations were not predictive of therapeutic outcomes. Conclusions: IL-32α activity is associated with worsening fibrosis scores in non-cirrhotic, chronic HCV patients.

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ERYTHROID DIFFERENTIATION IS SUPPRESSED BY RIBAVIRIN DURING COMBINATION THERAPY WITH PEGYLATED INTERFERON-α2A IN CHRONIC HEPATITIS C: AN IN VITRO AND IN VIVO STUDY

Digestive and Liver Disease ◽

10.1016/s1590-8658(09)60131-6 ◽

2009 ◽

Vol 41 ◽

pp. S51

Author(s):

G.M. Prati ◽

A. Aghemo ◽

L. Ronzoni ◽

M.G. Rumi ◽

S. Monico ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Combination Therapy ◽

Chronic Hepatitis C ◽

Erythroid Differentiation ◽

Pegylated Interferon ◽

In Vivo Study ◽

Interferon Α2a

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Interleukin-12 p40/p70 Ratio and In Vivo Responsiveness to IFN-α Treatment in Chronic Hepatitis C

Journal of Interferon & Cytokine Research ◽

10.1089/10799900152434303 ◽

2001 ◽

Vol 21 (7) ◽

pp. 453-461 ◽

Cited By ~ 20

Author(s):

G. Piazzolla ◽

C. Tortorella ◽

G. Fiore ◽

M. Fanelli ◽

A. Pisconti ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Interleukin 12

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63 In-vitro and in-vivo evaluation of HCV polymerase inhibitors as potential drug candidates for treatment of chronic hepatitis C infection

Journal of Hepatology ◽

10.1016/s0168-8278(04)90063-3 ◽

2004 ◽

Vol 40 ◽

pp. 23

Author(s):

S. Dagan ◽

E. Ilan ◽

S. Aviel ◽

O. Nussbaum ◽

E. Arazi ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Potential Drug ◽

Hepatitis C Infection ◽

In Vivo Evaluation ◽

Drug Candidates ◽

Polymerase Inhibitors

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Effect of alpha interferon (IFN-alpha) on 2'-5' oligoadenylate synthetase activity in peripheral blood mononuclear cells of patients with chronic hepatitis C: relationship to the antiviral effect of IFN-alpha.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.2.320 ◽

1996 ◽

Vol 40 (2) ◽

pp. 320-324 ◽

Cited By ~ 15

Author(s):

J M Pawlotsky ◽

A G Hovanessian ◽

F Roudot-Thoraval ◽

N Robert ◽

M Bouvier ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Chronic Hepatitis C ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Antiviral Effect ◽

Peripheral Blood Mononuclear ◽

Ifn Alpha

Alpha interferon (IFN-alpha) is, to date, the only treatment with proven efficacy in patients with chronic hepatitis C. However, less than 15% of the patients have a sustained response to IFN-alpha. Interferon acts through the induction of various cellular enzymes. Among them, the 2'-5' oligoadenylate synthetase (2-5OAS) is (at least in part) responsible for a direct antiviral effect of IFN-alpha. The aim of this study was to determine whether basal and IFN-alpha-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cells predict biochemical and virological responses to IFN-alpha in patients with chronic hepatitis C. 2-5OAS activity in peripheral blood mononuclear cells and the antiviral effect of IFN-alpha were studied in 36 patients with chronic hepatitis C (27 men and 9 women; mean age, 44.7 years). Basal in vivo 2-5OAS activity (mean +/- standard error of the mean) was 4.41 +/- 0.69 nmol/10(6) cells. It was significantly induced at month 3 of IFN-alpha therapy (18.07 +/- 2.74 nmol/10(6) cells; P = 0.0001). No significant differences were found in basal in vivo 2-5OAS activities, in IFN-alpha-induced/basal in vitro 2-5OAS activity ratios, in IFN-alpha-induced in vivo 2-5OAS activities, and in IFN-alpha-induced/basal in vivo 2-5OAS activity ratios between the patients with and without a biochemical response (normal alanine aminotransferase activity in serum) or a virological response (normal alanine aminotransferase activity in serum and negative hepatitis C virus RNA detection) at any step of the study. At month 3 of therapy, p69, which is considered to be the active isoform of 2-5OAS, was induced, as demonstrated by Western blot (immunoblot) analysis in 50% of the patients, and induction of the p100 isoform was observed in 70% of the patients. No significant relationship with the response to IFN-alpha therapy was observed. Our results suggest that a deficiency of the IFN-alpha-dependent 2-5OAS system, which could be genetically determined, is unlikely to be responsible for the failure to achieve biochemical and virological responses to IFN-alpha therapy in patients with chronic hepatitis C.

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