Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in Tcells from patients with multiple sclerosis

Interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) t hrough several immunomodulatory mechanisms that may involve augmentation of programmed cell death (apoptosis) of T lymphocytes. The anti-apoptosis pro tein FLIP (Fas-associated death domain-like interleukin-1 beta -converting enzyme inhibitory protein) has been recently identified as a potent regulat or of T lymphocyte susceptibility to apoptosis. In a prospective study, we evaluated the expression of FLIP and other apoptosis regulatory proteins in ex vivo activated T lymphocytes from MS patients, before and serially afte r treatment with interferon-beta. We also investigated the long-term effect s of interferon-beta on T cell apoptosis in a cross-sectional study of MS p atients receiving chronic drug therapy. Treatment with interferon-beta redu ced the expression of FLIP isoforms in activated T lymphocytes. This reduce d expression correlated with augmented T cell susceptibility to apoptosis a nd with clinical response to treatment. In contrast, interferon-beta therap y did not alter cellular expression of the anti-apoptotic protein Bcl-2. Th is downregulatory effect of interferon-beta on cellular FLIP expression was maintained following long-term therapy. Our findings suggest that interfer on-beta therapy exerts a regulatory effect on peripheral T lymphocytes thro ugh a pro-apoptosis mechanism that involves the downregulation of cellular FLIP expression. (C) 2001 Elsevier Science B.V. All rights reserved.