More MS news articles for August 2002

Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1

Journal of Neuroimmunology, Vol. 129 (1-2) (2002) pp. 205-215
Xuan Feng, Anthony L. Petraglia, Michael Chen, Paul V. Byskosh, Markus D. Boos and Anthony T. Reder a
Department of Neurology, MC-2030, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637, USA

Multiple sclerosis is an immune-mediated brain disease ameliorated by interferon-b therapy.

Immune responses to IFN-a and IFN-b are sometimes subnormal in MS peripheral blood mononuclear cells (MNCs), suggesting an underlying defect in type I IFN signaling.

We studied IFN-b regulation of mRNA and protein induction for IFN regulatory factor-1 (IRF-1) and IRF-2, which control multiple IFN-stimulated genes, and for 2´,5´-oligoadenylate synthetase (2´,5´-OAS) and MxA, which are antiviral proteins.

First, mRNA levels in resting MNC from untreated patients with clinically active MS contained IRF-1 at 38% of normal controls, 45% for IRF-2, 44% for 2´,5´-OAS (all p<0.005), and 46% for MxA protein (p<0.007).

Stable MS patients had intermediate levels of 2´,5´-OAS and MxA.

IFN-b-1b therapy increased IRF-1, IRF-2, and 2´,5´-OAS mRNA in resting MNCbut only up to levels seen in unstimulated control cells.

In untreated patients with active MS, serine phosphorylation of the STAT1 transcription factor was markedly reduced, suggesting a mechanism for the low levels of IFN-induced genes.

Secondly, in untreated patients with stable MS, culture with IFN-b induced excessive tyrosine phosphorylation of STAT1, and this correlated with low SHP1 tyrosine phosphatase levels.

Excessive P-Tyr-STAT1 responses could induce inflammatory cytokines and demyelination in MS, as in motheaten mice, which have defects in SHP-1 function.

Abnormal IFN signaling may predict the course of MS and responses to therapy.

© 2002 Elsevier Science B.V.