Systemic IFN-beta treatment induces apoptosis of peripheral immune cells in MS patients.
In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta 1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X(L), Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immunomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment.
Gniadek
Paul
P
Institute of Neuroimmunology, Neuroscience Research Center, Humboldt-University, NWFZ 2680, Charité, 10098 Berlin, Germany.
Aktas
Orhan
O
Wandinger
Klaus-Peter
KP
Bellmann-Strobl
Judith
J
Wengert
Oliver
O
Weber
Alexandra
A
von Wussow
Peter
P
Obert
Hans-Jürgen
HJ
Zipp
Frauke
F
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D053938:DNA Fragmentation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019204:GTP-Binding Proteins / Q000097:blood; D006801:Humans; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D064547:Myxovirus Resistance Proteins
D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins; D000068556:Interferon beta-1a