Reduced expression of the inhibitor of apoptosis proteins in T cells from patients with multiple sclerosis following interferon-beta therapy.
Treatment with interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The recently identified family of inhibitor of apoptosis (IAP) proteins is a potent regulator of cell death. The expression of IAP-1, IAP-2, and X-linked IAP (XIAP) is upregulated in mitogen stimulated T lymphocytes from MS patients, and this expression correlates with MS disease activity. In this study, we sought to evaluate the effect of interferon-beta on cellular expression of IAP proteins and other apoptosis regulatory molecules. In a prospective study, we evaluated the expression of IAP proteins, the anti-apoptosis Bcl-2 protein, and the death receptor Fas in in vitro stimulated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on cellular expression of these proteins and T lymphocyte apoptosis in a cross-sectional study of MS patients receiving drug therapy for a mean of 4.8 years. Treatment with interferon-beta reduced the expression of IAP-1, IAP-2 and XIAP in stimulated T lymphocytes. This reduced expression correlated with increased T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of Bcl-2 protein or the death receptor Fas. This downregulatory effect of interferon-beta on cellular expression of IAP proteins was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through an anti-apoptosis mechanism that involves the downregulation of cellular IAP proteins expression.
Sharief
M K
MK
Department of Neuroimmunology, Guy's, King's and St Thomas' School of Medicine, Hodgkin Building, Guy's Hospital, SE1 1UL, England, London, UK. m.k.sharief@kcl.ac.uk
Noori
M A
MA
Zoukos
Y
Y
D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008137:Longitudinal Studies; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D011446:Prospective Studies; D011506:Proteins / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012074:Remission Induction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor