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, Meng Liang Zhao, Mark Rivieccio, Shinyeop Choi, Erin Connolly, Yongmei Zhao, Osamu Takikawa, Celia F. Brosnan, Sunhee C. Lee

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Abstract

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-γ) but more potent than IFN-β in inducing IDO. PIC induction of IDO was mediated in part by IFN-β but not IFN-γ, and both NF-κB and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN-β) and secondary (IDO and viperin) response genes upon subsequent stimulation with PIC. In HIVE, the transcripts for TLR3, IFN-β, 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 stomatitis 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-β-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.

Original languageEnglish (US)
Pages (from-to)9838-9850
Number of pages13
JournalJournal of Virology
Volume81
Issue number18
DOIs
StatePublished - Sep 2007

Fingerprint

Toll-Like Receptor 3
Indoleamine-Pyrrole 2,3,-Dioxygenase
polyinosinic-polycytidylic acid
astrocytes
Astrocytes
Antiviral Agents
Ligands
interferons
Interferons
Interferon Regulatory Factor-3
HIV
Encephalitis
encephalitis
polyriboinosinic-polyribocytidylic acid
indoleamine 2,3-dioxygenase
ligands
Toll-like receptor 3
Tryptophan
tryptophan
nitric oxide

ASJC Scopus subject areas

  • Immunology

Cite this

Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I : C): Mechanism of induction and role in antiviral response. / Suh, Hyeon Sook; Zhao, Meng Liang; Rivieccio, Mark; Choi, Shinyeop; Connolly, Erin; Zhao, Yongmei; Takikawa, Osamu; Brosnan, Celia F.; Lee, Sunhee C.

In: Journal of Virology, Vol. 81, No. 18, 09.2007, p. 9838-9850.

Research output: Contribution to journalArticle

Suh, HS, Zhao, ML, Rivieccio, M, Choi, S, Connolly, E, Zhao, Y, Takikawa, O, Brosnan, CF & Lee, SC 2007, 'Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I: C): Mechanism of induction and role in antiviral response', Journal of Virology, vol. 81, no. 18, pp. 9838-9850. https://doi.org/10.1128/JVI.00792-07
Suh, Hyeon Sook ; Zhao, Meng Liang ; Rivieccio, Mark ; Choi, Shinyeop ; Connolly, Erin ; Zhao, Yongmei ; Takikawa, Osamu ; Brosnan, Celia F. ; Lee, Sunhee C. / Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I : C): Mechanism of induction and role in antiviral response. In: Journal of Virology. 2007 ; Vol. 81, No. 18. pp. 9838-9850.
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abstract = "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-γ) but more potent than IFN-β in inducing IDO. PIC induction of IDO was mediated in part by IFN-β but not IFN-γ, and both NF-κB and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN-β) and secondary (IDO and viperin) response genes upon subsequent stimulation with PIC. In HIVE, the transcripts for TLR3, IFN-β, 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 stomatitis 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-β-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.",
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T2 - C): Mechanism of induction and role in antiviral response

AU - Suh, Hyeon Sook

AU - Zhao, Meng Liang

AU - Rivieccio, Mark

AU - Choi, Shinyeop

AU - Connolly, Erin

AU - Zhao, Yongmei

AU - Takikawa, Osamu

AU - Brosnan, Celia F.

AU - Lee, Sunhee C.

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AB - 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-γ) but more potent than IFN-β in inducing IDO. PIC induction of IDO was mediated in part by IFN-β but not IFN-γ, and both NF-κB and interferon regulatory factor 3 (IRF3) were required. PIC also upregulated TLR3, thereby augmenting the primary (IFN-β) and secondary (IDO and viperin) response genes upon subsequent stimulation with PIC. In HIVE, the transcripts for TLR3, IFN-β, 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 stomatitis 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-β-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.

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