IL-23/IL-17 Axis in Chronic Hepatitis C and Non-Alcoholic Steatohepatitis-New Insight into Immunohepatotoxicity of Different Chronic Liver Diseases

Abstract

Considering the relevance of the research of pathogenesis of different liver diseases, we investigated the possible activity of the IL-23/IL-17 axis on the immunohepatotoxicity of two etiologically different chronic liver diseases. A total of 36 chronic hepatitis C (CHC) patients, 16 with (CHC-SF) and 20 without significant fibrosis (CHC-NSF), 19 patients with non-alcoholic steatohepatitis (NASH), and 20 healthy controls (CG) were recruited. Anthropometric, biochemical, and immunological cytokines (IL-6, IL-10, IL-17 and IL-23) tests were performed in accordance with standard procedure. Our analysis revealed that a higher concentration of plasma IL-23 was associated with NASH (p = 0.005), and a higher concentration of plasma IL-17A but a lower concentration of plasma IL-10 was associated with CHC in comparison with CG. A lower concentration of plasma IL-10 was specific for CHC-NSF, while a higher concentration of plasma IL-17A was specific for CHC-SF in comparison with CG. CHC-NSF and CHC-SF groups were distinguished from NASH according to a lower concentration of plasma IL-17A. Liver tissue levels of IL-17A and IL-23 in CHC-NSF were significantly lower in comparison with NASH, regardless of the same stage of the liver fibrosis, whereas only IL-17A tissue levels showed a difference between the CHC-NSF and CHC-SF groups, namely, a lower concentration in CHC-NSF in comparison with CHC-SF. In CHC-SF and NASH liver tissue, IL17-A and IL-23 were significantly higher in comparison with plasma. Diagnostic accuracy analysis showed significance only in the concentration of plasma cytokines. Plasma IL-6, IL-17A and IL-23 could be possible markers that could differentiate CHC patients from controls. Plasma IL-23 could be considered a possible biomarker of CHC-NSF patients in comparison with controls, while plasma IL-6 and IL-17-A could be biomarkers of CHC-SF patients in comparison with controls. The most sophisticated difference was between the CHC-SF and CHC-NSF groups in the plasma levels of IL-10, which could make this cytokine a useful biomarker of liver fibrosis.

Keywords: IL-23/IL-17 axis; chronic hepatitis C; immunohepatotoxicity; non-alcoholic steatohepatitis.

Figure 1

CHC-NSF: chronic hepatitis C with non-significant fibrosis, CHC-SF: chronic hepatitis C with significant fibrosis, NASH: non-alcoholic steatohepatitis, CG: control group, IL-6: interleukin 6. Median level of IL-6 in plasma and liver tissue of healthy controls and patients with liver diseases. Statistical difference was assessed using Kruskal–Wallis test. * p < 0.05 in comparison with CG; $ p < 0.05 in comparison with NASH; # p < 0.05 in comparison with CHC-NSF, ¥ p < 0.05 plasma levels in comparison with liver tissue levels (Post-hoc statistical difference using Mann–Whitney test); n (CG) = 20, n (NASH) = 19, n (CHC-NSF) = 20, n (CHC-SF) = 16.

Figure 2

CHC-NSF: chronic hepatitis C with non-significant fibrosis, CHC-SF: chronic hepatitis C with significant fibrosis, NASH: non-alcoholic steatohepatitis, CG: control group, IL-10: interleukin 10. Median level of IL-10 in plasma and liver tissue of healthy controls and patients with liver diseases. Statistical difference was assessed using Kruskal–Wallis test. * p < 0.05 in comparison with CG; $ p < 0.05 in comparison with NASH; # p < 0.05 in comparison with CHC-NSF; ¥ p < 0.05 plasma levels in comparison with liver tissue levels (Post-hoc statistical difference using Mann–Whitney test); n (CG) = 20, n (NASH) = 19, n (CHC-NSF) = 20, n (CHC-SF) = 16.

Figure 3

CHC-NSF: chronic hepatitis C with non-significant fibrosis, CHC-SF: chronic hepatitis C with significant fibrosis, NASH: non-alcoholic steatohepatitis, CG: control group, IL-17A: interleukin 17A. Median level of IL-17A in plasma and liver tissue of healthy controls and patients with liver diseases. Statistical difference was assessed using Kruskal–Wallis test. * p < 0.05 in comparison with CG; $ p < 0.05 in comparison with NASH; # p < 0.05 in comparison with CHC-NSF; ¥ p < 0.05 plasma levels in comparison with liver tissue levels (Post-hoc statistical difference using Mann–Whitney test); n (CG) = 20, n (NASH) = 19, n (CHC-NSF) = 20, n (CHC-SF) = 16.

Figure 4

CHC-NSF: chronic hepatitis C with non-significant fibrosis, CHC-SF: chronic hepatitis C with significant fibrosis, NASH: non-alcoholic steatohepatitis, CG: control group, IL-23: interleukin 23. Median level of IL-23 in plasma and liver tissue of healthy controls and patients with liver diseases. Statistical difference was assessed using Kruskal–Wallis test. * p < 0.05 in comparison with CG; $ p < 0.05 in comparison with NASH; ¥ p < 0.05 plasma levels in comparison with liver tissue levels (Post-hoc statistical difference using Mann–Whitney test); n (CG) = 20, n (NASH) = 19, n (CHC-NSF) = 20, n (CHC-SF) = 16.

Figure 5

ROC curve of plasma IL-10 as biomarker for distinguishing CHC-NSF and CHC-SF patients. CHC-NSF: chronic hepatitis C with non-significant fibrosis, CHC-SF: chronic hepatitis C with significant fibrosis, IL: interleukin, blue line: ROC curve; green line: baseline.