IFN-alpha induced IFN-gamma production of NK cells is not inhibited but enhanced by adenosine

Interferon alpha (IFNa) is produced by various cell types in response to viral infections and is used to treat HBV and HCV infection. To what extent an „immunomodulatory“ effect of IFNa contributes to its antiviral efficacy in viral hepatitis is poorly defined. We here aimed to explore in more detail the effects of IFNa on human NK cells. In particular we were interested in potential inhibitory molecules that could explain treatment failure. Based on our previous work, we tested whether adenosine could impair IFNa-induced activation of NK cells. Adenosine, a ribonucleoside produced by various cell types during inflammatory processes, has been shown to inhibit effector functions of different immune cells. We investigated the effects of IFNa and adenosine on IFN gamma (IFNg) production of human PBMC in vitro. Adenosine potently inhibited proliferation, IFNg production and cytotoxicity of PHA and SEB stimulated PBMC. However and surprisingly, the IFNg production was increased in a dose dependent manner when PBMC were cultured with adenosine together with IFNa. We gained evidence that this effect was mediated mainly via the A3 receptor by using various specific receptor agonists. Importantly, the increase of IFNg production was exclusively detected in NK cells but not in CD3+ positive cells. The effect was highly reproducible in healthy subjects but could also be detected in patients with hepatitis C as well as in individuals receiving treatment with PEG-IFNa and ribavirin. Conclusion: IFNa and adenosine differentially contribute to the regulation of immune responses during inflammation and antiviral therapy. Both compounds are inhibiting proliferation of T cells and NK cells and thus contribute to the prevention of overwhelming immune responses during acute infections. On the other hand, antiviral effector functions such as IFNg production are synergistically increased potentially leading to more efficient control of viral infections.