title: STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-alpha in the central nervous system.
abstract: 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-alpha 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-alpha 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-alpha 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 JAKSTAT pathway may protect against such IFN-alpha-mediated injury in the CNS.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C494228:Isgf3g protein, mouse; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors