Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1.
Multiple sclerosis is an immune-mediated brain disease ameliorated by interferon-beta therapy. Immune responses to IFN-alpha and IFN-beta are sometimes subnormal in MS peripheral blood mononuclear cells (MNCs), suggesting an underlying defect in type I IFN signaling. We studied IFN-beta 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-beta-1b therapy increased IRF-1, IRF-2, and 2',5'-OAS mRNA in resting MNC-but 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-beta 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.
Feng
Xuan
X
Department of Neurology, MC-2030, University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637, USA.
Petraglia
Anthony L
AL
Chen
Michael
M
Byskosh
Paul V
PV
Boos
Markus D
MD
Reder
Anthony T
AT
D015088:2',5'-Oligoadenylate Synthetase / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000328:Adult; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005260:Female; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use; D007372:Interferons / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000068576:Interferon beta-1b; D014443:Tyrosine; D012694:Serine; D016899:Interferon-beta; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; D019204:GTP-Binding Proteins; D000068556:Interferon beta-1a