Interferon alpha 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 sugges t 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), purif ied T cells and ATC of healthy volunteers were stimulated with various agen ts and the influence of IFN-alpha on Fas/FasL was assessed by mRNA and prot ein studies, The proportion of ATC undergoing AICD or anti-Fas-induced apop tosis 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 incre ased in PBMC and T cells co-stimulated with IFN-alpha and various agents, w hereas Fas surface expression was enhanced by IFN-alpha alone, IFN-alpha en hanced apoptosis induced by anti-Pas antibody and augmented AICD via the Fa s/FasL pathway. IFN-alpha-regulated AICD may contribute to lymphopenia obse rved 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.