J Neuroimmunol 2003 Apr;137(1-2):187-96
Gniadek P, Aktas O, Wandinger KP, Bellmann-Strobl J, Wengert O, Weber A, von Wussow P, Obert HJ, Zipp F.
Institute of Neuroimmunology, Neuroscience Research Center, Humboldt-University, NWFZ 2680, Charite, 10098, Berlin, Germany
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-beta1a 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.