Interferon-alpha (IFN-α) enhances cytotoxicity in healthy volunteers and chronic hepatitis C infection mainly by the perforin pathway

Abstract

Cell-mediated cytotoxicity is exerted via perforin and Fas ligand (FasL). We have recently shown that IFN-alpha up-regulates FasL expression in T cells isolated from healthy volunteers and augments activation-induced T cell death. Since the Fas/FasL system is implicated in the pathogenesis of hepatic failure and both molecules have been shown to be up-regulated in hepatitis C virus (HCV) infection, we studied whether cytotoxicity via the FasL system is enhanced by IFN-alpha and therefore could contribute to hepatic injury. We investigated FasL and perforin expression in peripheral blood mononuclear cells (PBMC) derived from HCV+ donors by Northern analysis and soluble FasL synthesis by ELISA. Natural killer (NK) cell and cytotoxic T lymphocyte (CTL) cytotoxicity was studied by 51Cr-release assays. IFN-alpha up-regulates FasL mRNA and protein synthesis in mitogen-activated PBMC of HCV+ individuals, as previously found in healthy subjects. Stimulation with IFN-alpha increases perforin mRNA levels in PBMC. In NK cytotoxicity assays, the enhancement of cytotoxicity by IFN-alpha is mainly due to the perforin pathway, while the FasL pathway plays only a minor role. In CTL cytotoxicity experiments neither the FasL nor the perforin pathway is further enhanced by IFN-alpha. Our data suggest that up-regulation of perforin by IFN-alpha results in elevated cytotoxicity, suggesting that IFN-alpha might support elimination of virally infected cells via this pathway. In contrast, the major effect of IFN-alpha on the Fas/FasL system might be the enhanced elimination of activated T cells as a means of finally limiting a T cell response.

The addition of ribavirin to interferon-alpha therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism

“…In our cases, RIBA could induce hypothyroidism by Th1-dependent activation of CD8þ T lymphocytes which induce cellular destruction predominantly by the perforin pathway (31). By the same token, IFN-a favors such a mechanism by enhancing the expression of perforin molecules in peripheral lymphocytes, as recently demonstrated in an in vitro model (32). The thyroid cell damage in RIBA-induced hypothyroidism could also be due to a complement-mediated injury.…”

Partial Contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)/TRAIL Receptor Pathway to Antitumor Effects of Interferon-α/5-Fluorouracil against Hepatocellular Carcinoma

“…activated NK cells (45,46), additional studies are needed to clarify the contribution of these molecules.…”

Immunopathogenesis of Hepatitis C Virus Infection

“…However, studies of acute hepatitis C patients don’t universally indicate that the magnitude of NK cell cytotoxicity and IFNγ production clearly are associated with virological outcome, with both CD16 + CD56 dim and CD16 − CD56 bright subsets showing activation (112–114). Controversy exists about the impact of chronic HCV-infection of NK cell cytotoxicity (115, 116). While the frequency of peripheral NK cells appears to be decreased in chronic HCV, particularly among CD16 + CD56 dim NK cells, no difference in NK cell cytotoxicity appears to be present between chronic HCV patients and healthy donors or resolved patients (117–120).…”