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Unformatted text preview: J OURNAL OF VIROLOGY, Sept. 2007, p. 9838–9850 Vol. 81, No. 18 0022-538X/07/$08.00 doi:10.1128/JVI.00792-07 Copyright © 2007, American Society for Microbiology. All Rights Reserved. Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response Hyeon-Sook Suh, 1 Meng-Liang Zhao, 1 Mark Rivieccio, 1 Shinyeop Choi, 1 Erin Connolly, 1 Yongmei Zhao, 1 Osamu Takikawa, 2 Celia F. Brosnan, 1 and Sunhee C. Lee 1 * Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, 1 and National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Japan 2 Received 12 April 2007/Accepted 2 July 2007 Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism and has been implicated in neurotoxicity and suppression of the antiviral T-cell response in HIV encephalitis (HIVE). Here we show that the Toll-like receptor 3 (TLR3) ligand poly(I:C) (PIC) induces the expression of IDO in human astrocytes. PIC was less potent than gamma interferon (IFN- ) but more potent than IFN- in inducing IDO. PIC induction of IDO was mediated in part by IFN- but not IFN- , and both NF- B and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN- ) and secondary (IDO and viperin) response genes upon subsequent stimu- lation with PIC. In HIVE, the transcripts for TLR3, IFN- , IDO, and viperin were increased and IDO immunoreactivity was detected in reactive astrocytes as well as macrophages and microglia. PIC caused suppression of intracellular replication of human immunodeficiency virus pseudotyped with vesicular stoma- titis virus G protein and human cytomegalovirus in a manner dependent on IRF3 and IDO. The involvement of IDO was demonstrated by partial but significant reversal of the PIC-mediated antiviral effect by IDO RNA interference and/or tryptophan supplementation. Importantly, the cytokine interleukin-1 abolished IFN- - induced IDO enzyme activity in a nitric oxide-dependent manner without suppressing protein expression. Our results demonstrate that IDO is an innate antiviral protein induced by double-stranded RNA and suggest a therapeutic utility for PIC in human viral infections. They also show that IDO activity can be dissociated from protein expression, indicating that the local central nervous system cytokine and nitric oxide environment determines IDO function. In the central nervous system (CNS), astrocytes play an important role as regulators of extracellular electrolyte and neurotransmitter balance, as well as in the establishment and maintenance of the blood-brain barrier. Together with micro- glia, astrocytes are also important modulators of CNS immune and inflammatory reactions (20, 37, 38), participating in both innate and acquired immune responses. Recently, it has been well established that astrocytes express certain members of the...
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This note was uploaded on 11/01/2010 for the course A B taught by Professor C during the Spring '10 term at HKU.
- Spring '10