Cytokine mRNA expression in hepatitis C virus infection: TH1 predominance in patients with chronic hepatitis C and TH1–TH2 cytokine profile in subjects with self‐limited disease

Abstract

Many determinants of the immune response have been implied in the pathogenesis of chronic hepatitis C. TH1 and TH2 cytokines play a prominent role in viral infections and a dysregulation of these cytokines could account for viral persistence and evolution of chronic disease. To explore a possible TH1 and TH2 cytokine dysregulation resulting in the inability to terminate hepatitis C virus (HCV) infection, we studied TH1 [interferon (IFN)-gamma, interleukin (IL)-2] and TH2 (IL-4, IL-10) mRNA expression of peripheral blood mononuclear cells (PBMC) in response to NS3 HCV antigen stimulation, in 31 untreated patients with chronic hepatitis C and 29 subjects with self-limited disease. After a 48 h culture of PBMC, total RNA isolation was performed and complementary DNA was prepared by reverse transcription. mRNA levels were quantified by real-time polymerase chain reaction using a standard curve formed after cloning each cytokine gene and a reference gene using recombinant DNA technology in a specific plasmid vector. In the patients group, mRNA expression of IFN-gamma, IL-2 and IL-4 but not IL-10 was detected, IFN-gamma being the predominant cytokine expressed. All four cytokines were expressed in subjects with self limited disease, however levels of IFN-gamma were lower and a significant higher expression of IL-10 compared to patients was found. There was a significant correlation between IFN-gamma mRNA expression levels and stage of fibrosis. Our findings show that in chronic hepatitis C, TH1 cytokines predominate and correlate to liver immunopathology. Furthermore, subjects with self-limited disease, maintain the ability to respond to HCV antigens for a long time after disease resolution.

Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients

“…Nowadays, it is well established that the host immune response, which is regulated by the host genetic background, plays a prominent role in the natural history of the disease [3,8,52]. A positive correlation between a high level of pro-inflammatory cytokines secreted in response to HCV-related liver injury, and an increased necroinflammatory activity, liver fibrosis or cirrhosis was previously reported [8,10,11,53]. Cytokine production varies among individuals and is associated with certain mutations within the coding and the regulatory regions [27].…”

“…Clinical research showed the prominent role of T helper cell type 1 (Th1) or pro-inflammatory and type 2 (Th2) or anti-inflammatory cytokines in the pathogenesis of chronic hepatitis C. Indeed, a positive correlation between Th1 cytokine levels or Th1-type cell percentage and histological fibrosis or progressive liver injury in chronic hepatitis C was detected [7]. On the contrary, Th2 cytokines modulate self-inflicted injury by suppressing the Th1 response leading to milder forms of chronic hepatitis C [8][9][10][11]. Actually, in the absence of an efficient eradication of the infected cells, the continuing inflammation is responsible for liver damage leading to fibrosis and ultimately cirrhosis [12,13].…”

Hepatitis C: Viral Features and Clinical Aspects

“…However, they produce intrahepatic IFN-γ, which has antiviral action and is essential in the action of T-cells [47][48][49].…”

“…This mechanism can eliminate infected hepatocytes, thereby limiting viral replication and contributing to liver tissue damage during the immune response. The hepatitis C virus has the ability to infect not only hepatocytes but also immune cells such as B and T lymphocytes [48].…”

IL-8 Is Associated with Non-Viremic State and IFN-γ with Biochemical Activity in HCV-Seropositive Blood Donors

“…However, it has been suggested that a strong proinflammatory cytokine response could play an important role in the development of hepatic injury in patients with chronic hepatitis C, and therefore, apart from contributing to viral clearance, this polarized immunological profile may contribute to the pathogenesis of liver disease. Subjects with a self-limiting HCV infection appear to maintain their ability to mount both an inflammatory and a regulatory cytokine response for extended periods following viral clearance [7] .…”