Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1 - PubMed (original) (raw)
Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1
Xuan Feng et al. J Neuroimmunol. 2002 Aug.
Abstract
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.
Similar articles
- IFN-beta induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7.
Sancéau J, Hiscott J, Delattre O, Wietzerbin J. Sancéau J, et al. Oncogene. 2000 Jul 13;19(30):3372-83. doi: 10.1038/sj.onc.1203670. Oncogene. 2000. PMID: 10918594 - Cytokine-like effects of prolactin in human mononuclear and polymorphonuclear leukocytes.
Dogusan Z, Hooghe R, Verdood P, Hooghe-Peters EL. Dogusan Z, et al. J Neuroimmunol. 2001 Nov 1;120(1-2):58-66. doi: 10.1016/s0165-5728(01)00420-9. J Neuroimmunol. 2001. PMID: 11694320 - The growing family of interferon regulatory factors.
Nguyen H, Hiscott J, Pitha PM. Nguyen H, et al. Cytokine Growth Factor Rev. 1997 Dec;8(4):293-312. doi: 10.1016/s1359-6101(97)00019-1. Cytokine Growth Factor Rev. 1997. PMID: 9620643 Review. - Interferon regulatory factors: growth control and histone gene regulation--it's not just interferon anymore.
Vaughan PS, van Wijnen AJ, Stein JL, Stein GS. Vaughan PS, et al. J Mol Med (Berl). 1997 May;75(5):348-59. doi: 10.1007/s001090050120. J Mol Med (Berl). 1997. PMID: 9181476 Review.
Cited by
- FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis.
Jonnalagadda D, Kihara Y, Groves A, Ray M, Saha A, Ellington C, Lee-Okada HC, Furihata T, Yokomizo T, Quadros EV, Rivera R, Chun J. Jonnalagadda D, et al. Cell Rep. 2023 Dec 26;42(12):113545. doi: 10.1016/j.celrep.2023.113545. Epub 2023 Dec 7. Cell Rep. 2023. PMID: 38064339 Free PMC article. - Ifit2 restricts murine coronavirus spread to the spinal cord white matter and its associated myelin pathology.
Sharma M, Chakravarty D, Hussain A, Zalavadia A, Burrows A, Rayman P, Sharma N, Kenyon LC, Bergmann C, Sen GC, Das Sarma J. Sharma M, et al. J Virol. 2023 Aug 31;97(8):e0074923. doi: 10.1128/jvi.00749-23. Epub 2023 Jul 28. J Virol. 2023. PMID: 37504572 Free PMC article. - ADAR Expression and Single Nucleotide Variants in Multiple Sclerosis Patients Affect the Response to Interferon Beta Therapy.
Fakhr F, Shaygannejad V, Khorrami M, Saberi L, Mirmosayyeb O, Sadeghi E, Kheirollahi M. Fakhr F, et al. Glob Med Genet. 2023 Jul 10;10(3):164-171. doi: 10.1055/s-0043-1771001. eCollection 2023 Sep. Glob Med Genet. 2023. PMID: 37501759 Free PMC article. - The value of Interferon β in multiple sclerosis and novel opportunities for its anti-viral activity: a narrative literature review.
Bellucci G, Albanese A, Rizzi C, Rinaldi V, Salvetti M, Ristori G. Bellucci G, et al. Front Immunol. 2023 Jun 2;14:1161849. doi: 10.3389/fimmu.2023.1161849. eCollection 2023. Front Immunol. 2023. PMID: 37334371 Free PMC article. Review. - Breaking down the cellular responses to type I interferon neurotoxicity in the brain.
Viengkhou B, Hofer MJ. Viengkhou B, et al. Front Immunol. 2023 Feb 3;14:1110593. doi: 10.3389/fimmu.2023.1110593. eCollection 2023. Front Immunol. 2023. PMID: 36817430 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous