Elevated Levels of Interleukin-8 in Serum Are Associated with Hepatitis C Virus Infection and Resistance to Interferon Therapy

Abstract

Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). We have recently found that the HCV NS5A protein induces expression of the proinflammatory chemokine IL-8 to partially inhibit the antiviral actions of IFN in vitro. To extend these observations, in the present study we examined the relationship between levels of IL-8 in serum, HCV infection, and biochemical response to IFN therapy. Levels of IL-8 were significantly elevated in 132 HCV-infected patients compared to levels in 32 normal healthy subjects and were also significantly higher in patients who did not respond to IFN therapy than in patients who did respond to therapy. This study suggests that HCV-induced changes in levels of chemokine and cytokine expression may be involved in HCV antiviral resistance, persistence, and pathogenesis.Chronic hepatitis C virus (HCV) infection is a significant clinical problem throughout the world. About 85% of people infected with HCV develop chronic infection, and approximately 70% of patients develop histological evidence of chronic liver disease (9).Interferon (IFN) and the guanosine analogue ribavirin are widely used treatments for chronic HCV infection (5,11,17). However, as many as 60% of patients with high-titer HCV genotype 1 infections remain nonresponsive to combination therapy.The HCV NS5A protein has been implicated in the resistance of HCV to antiviral therapy (reviewed in reference 14). We have recently found that NS5A induces the CXC chemokine interleukin 8 (IL-8) to inhibit the antiviral actions of IFN in vitro (15). To investigate the clinical significance of these results, in this study we investigated the relationship among levels of IL-8 and tumor necrosis factor alpha (TNF-␣) (a potent inducer of ) in serum, HCV infection, and response to IFN therapy.One hundred thirty-two patients from Saudi Arabia with hepatitis C disease were studied. Diagnosis was reached using appropriate serological, virological, biochemical, and histological criteria. All sera from patients diagnosed to have chronic hepatitis C showed elevated liver enzymes, tested positive for anti-HCV antibodies by a second-generation enzyme-linked immunosorbent assay (ELISA), and were confirmed to be reactive with HCV recombinant immunoblot assay-2. Patients with hepatitis B surface antigen positivity, autoimmune disease, alcohol-or drug-induced liver diseases, hepatic failure, decompensated cirrhosis, schistosoma mansoni, or hematological abnormalities were excluded from the study. Genotypes were not determined, although the predominant HCV genotypes in Saudi Arabia are genotype 4 and 1 (2, 19). IFN-␣2a was administered intramuscularly three times per week at 3 million U per dose. The study was performed with the approval of the King Faisal Specialist Hospital and Research Centre research advisory council. Response to therapy was assessed biochemically based on normalization of alanine aminotransferase values 6 months after termination of therapy.To measure IL-8 ...

Effects of HCV Treatment on Cytokine Expression During HCV/HIV Coinfection

“…12,13,15,16 These data suggest that serum levels of cytokines, such as IL-8, TNF-α, and TGF-β1, might be important predictors of the virologic response to HCV therapy. In the present analysis, we measured cytokine levels to determine if cytokine expression was also associated with HCV virologic, histologic, or biochemical response among HCV/HIV-coinfected persons.…”

“…4 There is growing evidence that cytokine expression is also linked to HCV treatment response, with lower baseline levels generally correlated with virologic response. [4][5][6][7][8][9][10][11][12][13] Thus, certain cytokines may be useful as easily measured, predictive markers of treatment response.…”

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

“…IFN-γ is clearly augmented in the serum of chronic hepatitis C patients (Tilg et al 1992, Cacciarelli et al 1996, Kamal et al 2004) and its increase has been correlated with an increase in the severity of disease (Gonzalez-Peralta et al 1994). Moreover, an increased expression of IL-1, IL-2, IL-6, IL-10 and IL-18 has been documented in either the blood or liver of chronically HCV infected patients (Makris et al 1994, Schvoerer et al 2003, Hassan et al 1997, Oyanagi et al 1999, Polyak et al 2001. Nonetheless, most studies have been limited by a reduced sample size, resulting in a lack of statistical power.…”

Pathogenesis of hepatitis C: HCV consensus 2007

“…The levels of cytokines such as IFN-γ, TNF-α, IL-6 and IL-8 are elevated in individuals with chronic hepatitis C [74][75][76][77][78][79][80][81][82], and some authors have shown that this increase is proportional to the extent of the damage, histologically [26,76,83,84].…”