STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-α in the central nervous system

被引:49
作者
Wang, JP
Schreiber, RD
Campbell, IL
机构
[1] Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA
[2] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA
关键词
D O I
10.1073/pnas.252454799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Although signal transducer and activator of transcription 1 (STAT1) is an essential signaling molecule in many IFN-alpha-regulated processes, some biological responses to IFN-alpha can occur independently of STAT1. To establish the role of STAT1 in mediating the biological actions of IFN-a in the CNS, transgenic mice [termed glial fibrillary acidic protein (GFAP)-IFN-alpha] with astrocyte production of IFN-alpha were bred to be null for the STAT1 gene. Surprisingly, GFAP-IFN-alpha mice deficient for STAT1 developed earlier onset and more severe neurological disease with increased lethality compared with GFAP-IFN-alpha mice sufficient for STAT1. Whereas the brain of 2- to 3-month-old GFAP-IFN-alpha mice showed little, if any abnormality, the brain from GFAP-IFN-a mice deficient for STAT1 had severe neurodegeneration, inflammation, calcification with increased apoptosis, and glial activation. However, the cerebral expression of a number of IFN-regulated STAT1-dependent genes increased in GFAP-IFN-a mice but was reduced markedly in GFAP-IFN-alpha STAT1-null mice. Of many other signaling molecules examined, STAT3 alone was activated significantly in the brain of GFAP-IFN-alpha STAT1 null mice. Thus, in the absence of STAT1, alternative signaling pathways mediate pathophysiological actions of IFN-alpha in the living brain, giving rise to severe encephalopathy. Finally, STAT1 or a downstream component of the JAK/STAT pathway may protect against such IFN-alpha-mediated injury in the CNS.
引用
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页码:16209 / 16214
页数:6
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