Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system.
The prime anti-viral cytokine interferon-alpha (IFN-alpha) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-alpha treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-alpha have been described, it remains unresolved whether or not systemic IFN-alpha acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-alpha receptor signaling and found that intraperitoneal administration of mouse IFN-alpha, but not human IFN-alpha, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-alpha-activated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-alpha challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-alpha in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-alpha therapy.
Wang
J
J
Department of Pharmacology, University of Missouri-Kansas City, Kansas City, MO 64108, USA. wangjp@umkc.edu
Campbell
I L
IL
Zhang
H
H
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000378:metabolism; D013997:Time Factors
D007155:Immunologic Factors; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse