High Plasma Interleukin-18 Levels Mark the Acute Phase of Hepatitis C Virus Infection

Hepatitis C virus (HCV) is among the major etiologic agents of chronic liver disease. An estimated 170 million chronic infections with this virus occur worldwide, with a 1%–2% prevalence rate in most countries [1]. HCV evades clearance mechanisms and establishes persistent infection (PI) in the majority of infections, leading to cirrhosis in 5%–25% and hepatocellular carcinoma in 2% of infected persons [2, 3]. The outcome of infection is determined by early events in the virus–host interaction because failure to control HCV within the first 120 days of infection is strongly associated with PI [3]. Unfortunately, investigating early HCV pathogenesis and the mechanism underlying spontaneous control of HCV has been severely hindered by the difficulty in identifying persons acutely infected with HCV because most are asymptomatic during this period [3]. Proinflammatory cytokines, including interleukin (IL) 18, have been shown to play a role in control of viral infections [4]. In murine models of herpes simplex virus and vaccinia virus infections, IL-18 deficiency generated either by gene knockout or cytokine neutralization renders animals more susceptible to infection [5–7]. In humans, along with other inflammatory cytokines, IL-18 is elevated in persons with uncontrolled HIV and falls as the virus is suppressed by antiretroviral therapy [8, 9]. Associations between IL-18 gene polymorphisms and hepatitis B virus clearance have been observed in humans [10], and IL-18 has been shown to inhibit HBV replication in vivo in the livers of transgenic mice [11]. IL-18 is a member of the IL-1 cytokine family and is structurally related to IL-1β, and both are associated with the inflammasome [12]. IL-18 favors Th1 polarization and induces the expression of other proinflammatory cytokines, including nitric oxide, Fas ligand, and several chemokines. In addition to its role in infectious diseases, elevated serum IL-18 levels have been found in patients with autoimmune diseases, acute graft-versus-host disease, hematological malignancies, sepsis, and inflammatory liver diseases, suggesting a fundamental role in immunity [4]. The role of IL-18 in the pathogenesis of HCV remains unclear. Genetic associations between single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (A/A or C/A genotype at [–607] rs1946518 and G/C or C/C genotype at [–137] rs187238) and spontaneous HCV clearance have been reported in African-American injection drug users (IDUs) [13]. In small cross-sectional studies, serum IL-18 levels 3–4 times higher than those in healthy controls have been observed in persons with chronic HCV and cirrhosis due to HCV [14–17]. The levels appear to decrease after successful treatment with interferon (IFN)-α–containing regimens [17]. In one study, subjects with HCV also had higher IL-18 levels than did those with nonalcoholic fatty liver disease, a nonviral cause of liver disease [15]. Additional cytokine-associated SNPs associated with increased likelihood of spontaneous HCV clearance include rs3750912 (IL-18 binding protein) [18] and the C/C haplotype at rs12979860 SNP (IL-28B) [19]. However, the mechanism underlying these associations remains unclear. The present study was undertaken to determine the point during HCV infection at which IL-18 becomes elevated, whether plasma levels of other proinflammatory cytokines are altered in HCV-infected individuals, whether serum IL-18 levels differ before and during HCV infection based on SNP polymorphisms in the IL-18 promoter, and whether serum IL-18 level correlates with HCV RNA levels, liver inflammation, or outcome of infection.