1. ¹Department of Pharmacology, University of Missouri-Kansas City, Kansas City, MO, USA
2. ²School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, Australia

Correspondence: Dr J Wang, Department of Pharmacology, University of Missouri-Kansas City, 2411 Holmes Street, Room M3-123, Kansas City, MO 64108, USA. E-mail: wangjp@umkc.edu

Received 24 October 2006; Revised 29 March 2007; Accepted 3 April 2007; Published online 8 May 2007.

Abstract

The prime anti-viral cytokine interferon- (IFN-) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN- treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN- have been described, it remains unresolved whether or not systemic IFN- acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN- receptor signaling and found that intraperitoneal administration of mouse IFN-, but not human IFN-, 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--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- challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN- in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN- therapy.