Interferon beta-1a induces tumor necrosis factor receptor 1 but decreases tumor necrosis factor receptor 2 leukocyte mRNA levels in relapsing-remitting multiple sclerosis.
OBJECTIVE
Members of the tumor necrosis factor (TNF) receptor superfamily play a major role in the pathogenesis of multiple sclerosis. To elucidate the role of TNF receptors, in 53 relapsing-remitting multiple sclerosis patients, we measured the TNF receptor 1 and receptor 2 (TNF-R1 and TNF-R2) mRNA levels in peripheral blood leukocytes in natural history (n = 27) and during administration of interferon (IFN) beta-1a (n = 26).


METHODS
Every 3 months for the duration of 1 year peripheral blood leukocytes were investigated by quantitative reverse transcription polymerase chain reaction. Every 6 months, MRI scans of the brain were analyzed semiquantitatively.


RESULTS
At baseline, clinical expanded disability status scale score and TNF-R1 mRNA level were correlated. In the therapy group, the difference between T2 lesion load at baseline and after 12 months correlated negatively with the difference between TNF-R1 mRNA level at baseline and after 12 months. Subcutaneously applied IFN beta increased the amount of TNF-R1 mRNA, but partly decreased the amount of TNF-R2 mRNA in clinically and subclinically defined responders to therapy after 1 year compared to baseline.


CONCLUSIONS
This result might support the notion that due to different signal transduction properties of both receptors in the natural course of multiple sclerosis, TNF-alpha signaling in leukocytes via TNF-R1 might be beneficial, but detrimental via proinflammatory TNF-R2: part of the therapeutic efficacy of current first-line standard therapy with IFN might be due to the modulation of signal transduction pathways.
Reuss
Reinhard
R
Department of Neurology, Justus Liebig University Giessen, Giessen, Germany. Reinhard.Reuss@neuro.med.uni-giessen.de
Pohle
Susanne
S
Retzlaff
Kerstin
K
Hemberger
Jürgen
J
Oschmann
Patrick
P
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000276:Adjuvants, Immunologic; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D000068556:Interferon beta-1a