Interferon α augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression

Interferon a (IFN-alpha) plays a prominent role in the therapy of a variety of diseases. The Fas/FasL system is crucial for the cytotoxic function and the peripheral elimination of activated T lymphocytes (ATC) by a mechanism referred to as activation-induced cell death (AICD), Recent studies suggest a link between IFN-alpha, the 2', 5'- oligoadenylate system and apoptosis, We therefore asked whether IFN-a is able to regulate the Fas/FasL pathway and thereby affects AICD, Peripheral blood mononuclear cells (PBMC), purified T cells and ATC of healthy volunteers were stimulated with various agents and the influence of IFN-alpha on Fas/FasL was assessed by mRNA and protein studies, The proportion of ATC undergoing AICD or anti-Fas-induced apoptosis was determined by FITC-annexin V staining and propidium iodide uptake. IFN-alpha upregulated mRNA expression of Fas and Fast in activated PBMC, Furthermore the concentration of the soluble form of Fast (sFasL) was increased in PBMC and T cells co-stimulated with IFN-alpha and various agents, whereas Fas surface expression was enhanced by IFN-alpha alone, IFN-alpha enhanced apoptosis induced by anti-Pas antibody and augmented AICD via the Fas/FasL pathway. IFN-alpha-regulated AICD may contribute to lymphopenia observed during IFN-alpha therapy. Our data further support that IFN-alpha is a multifunctional cytokine with profound effects on the immune cascades. (C) 1999 Academic Press.