期刊
CLINICAL IMMUNOLOGY
卷 133, 期 1, 页码 27-44出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.clim.2009.05.019
关键词
CNS demyelination; Autoimmunity; Inflammation; Cytokine signaling; Signal Transducers and Activators of Transcription (STAT); Nuclear factor kappa-B (NF-kappa B); Peripheral immune cells; Interferon-beta therapy; Protein tyrosine phosphatase; EAE/TMEV
类别
资金
- National Multiple Sclerosis Society [RG2569C5]
- NIH [NS041593]
- Serono, Inc.
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS041593] Funding Source: NIH RePORTER
Interferon-beta is a current treatment for multiple sclerosis (MS). Interferon-beta is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon beta-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-kappa B, which are known SHP-1 targets. Interferon-beta treatment in vivo resulted in decreased NF-kappa B and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-beta treatment that correlated with decreased NF-kappa B and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-l treatment, indicating that SHP-1 is a predominant mediator of interferon-l activity. In conclusion, interferon-beta. treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis. (C) 2009 Elsevier Inc. All rights reserved.
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