Interferon-gamma is associated with hepatic dysfunction in fibrosis, cirrhosis, and hepatocellular carcinoma

Abstract

The relation between interferon-gamma (IFN-γ) levels and the severity of liver diseases through fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) has not been fully clarified. Thus, we aimed to characterize IFN-γ levels in liver-diseased patients. IFN-γ levels were determined by Western-blot and ELISA in sera from 30 healthy individuals, 53 patients with non-significant fibrosis (F0-F1), 47 with moderate/severe fibrosis (F2-F3), 44 cirrhotic patients (F4), and 50 with HCC. Enhanced levels of IFN-γ were associated with the progression of liver disease. The differences were statistically significant (P < 0.0001) when patients with F2-F3, F4, or HCC were compared with F0-F1 or healthy controls. The increase in IFN-γ was associated with HCC (OR = 0.98, 95% CI 0.97-0.99, P = 0.002). There was no statistically significant association between IFN-γ levels and HCV-RNA (IU/ml) (r = 0.1, P = 0.43) or HCV-NS4 (µg/mL) (r = 0.1, P = 0.17). There was significant (P < 0.0001) association between IFN-γ levels and the fibrosis stages and activity, albumin, platelet count, total bilirubin, and international normalized ratio (INR). In conclusion, elevated concentrations of IFN-γ represent a characteristic feature of liver disease severity regardless of underlying disease. Significant correlations with indices of hepatic dysfunction suggest that enhanced IFN-γ levels represent a consequence of liver dysfunction rather than of inflammatory disease.

Enhanced activation of human NK cells by drug-exposed hepatocytes

“…Exogenous IFN-γ had the same effect, while depletion of NK cells enhanced the proliferation of hepatocytes (Sun and Gao 2004). In humans elevated levels of IFN-γ correlated with liver disease severity regardless of the underlying cause (Attallah et al 2016). Taken together, these studies indicate that IFN-γ might be beneficial during the early stages of liver damage, but could have a negative effect during advanced stages of liver disease and liver regeneration.…”

Therapeutic Potential of OMe-PS-miR-29b1 for Treating Liver Fibrosis

“…Several reports conclude that its elevated concentration represents a characteristic feature of liver disease severity in cirrhosis patients and pre-clinical models. 53,54 Alternatively, IFN-g has been reported to exhibit potent anti-fibrotic activity. 55,56 We found elevated IFN-g protein levels in CBDL mouse serum, and its levels were significantly reduced with OMe-PS-miR-29b1 micelle treatment ( Figure 6B).…”

Natural Killer Cell–Derived Interferon‐Gamma Promotes Hepatocellular Carcinoma Through the Epithelial Cell Adhesion Molecule–Epithelial‐to‐Mesenchymal Transition Axis in Hepatitis B Virus Transgenic Mice

“…Conversely, long‐term elevated levels of IFN‐γ when working together with tumor necrosis factor alpha (TNF‐α) resulted in significantly increased susceptibility to malignant transformation in mesenchymal stem cells through nuclear factor kappa B (NF‐κB)–mediated oncogene activation . In humans, increased IFN‐γ is associated with HCC, as a consequence of liver dysfunction . HBsAg‐positive hepatocytes are extraordinarily sensitive to the cytolytic effect of IFN‐γ .…”

“…(18) In humans, increased IFN-γ is associated with HCC, as a consequence of liver dysfunction. (19) HBsAgpositive hepatocytes are extraordinarily sensitive to the cytolytic effect of IFN-γ. (10,11,20) Investigating whether IFN-γ derived from innate immune cells is related to HBV-associated HCC is warranted.…”