Interferon-beta therapy downregulates the anti-apoptosis protein FLIP in T cells from patients with multiple sclerosis.
Interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that may involve augmentation of programmed cell death (apoptosis) of T lymphocytes. The anti-apoptosis protein FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) has been recently identified as a potent regulator 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 after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on T cell apoptosis in a cross-sectional study of MS patients receiving chronic drug therapy. Treatment with interferon-beta reduced the expression of FLIP isoforms in activated T lymphocytes. This reduced expression correlated with augmented T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of the anti-apoptotic protein Bcl-2. This downregulatory effect of interferon-beta on cellular FLIP expression was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through a pro-apoptosis mechanism that involves the downregulation of cellular FLIP expression.
Sharief
M K
MK
Department of Neuroimmunology, Guy's, King's and St Thomas' School of Medicine, Guy's Hospital, Hodgkin Building, London, SE1 9RT, UK. m.k.sharief@kcl.ac.uk
Semra
Y K
YK
Seidi
O A
OA
Zoukos
Y
Y
D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage* / Q000009:adverse effects; D047908:Intracellular Signaling Peptides and Proteins; D008137:Longitudinal Studies; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011446:Prospective Studies; D012074:Remission Induction / Q000379:methods; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019014:fas Receptor; D016899:Interferon-beta; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases