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Journal of Virology, July 2009, p. 6757-6768, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02570-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus E3 Suppresses Expression of Diverse Cytokines through Inhibition of the PKR, NF-{kappa}B, and IRF3 Pathways{triangledown}

Chad Myskiw,1 Janilyn Arsenio,1 Rebekah van Bruggen,2 Yvon Deschambault,2 and Jingxin Cao1,2*

National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, Canada R3E 3R2,2 Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada R3T 2N21

Received 12 December 2008/ Accepted 8 April 2009

The vaccinia virus double-stranded RNA binding protein E3 has been demonstrated to inhibit the expression of cytokines, including beta interferon (IFN-β) and tumor necrosis factor alpha (TNF-{alpha}). However, few details regarding the molecular mechanisms of this inhibition have been described. Using real-time PCR arrays, we found that E3 suppressed the induction of a diverse array of cytokines representing members of the IFN, interleukin (IL), TNF, and transforming growth factor cytokine families. We discovered that the factor(s) responsible for the induction of IL-6, TNF-{alpha}, and inhibin beta A (INHBA) was associated with the early and late phases of virus infection. In contrast, the factor(s) which regulates IFN-β induction was associated with the late phase of replication. We have found that expression of these cytokines can be induced by transfection of cells with RNA isolated from vaccinia virus-infected cells. Moreover, we provide evidence that E3 antagonizes both PKR-dependent and PKR-independent pathways to regulate cytokine expression. PKR-dependent activation of p38 and NF-{kappa}B was required for vaccinia virus-induced INHBA expression, whereas induction of TNF-{alpha} required only PKR-dependent NF-{kappa}B activation. In contrast, induction of IL-6 and IFN-β was largely PKR independent. IL-6 induction is regulated by NF-{kappa}B, while IFN-β induction is mediated by IFN-β promoter stimulator 1 and IFN regulatory factor 3/NF-{kappa}B. Collectively, these results indicate that E3 suppresses distinct but interlinked host signaling pathways to inhibit the expression of a diverse array of cytokines.

* Corresponding author. Mailing address: National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB, Canada R3E 3R2. Phone: (204) 789-6052. Fax: (204) 789-2082. E-mail: jingxin_cao{at}phac-aspc.gc.ca

{triangledown} Published ahead of print on 15 April 2009.

Journal of Virology, July 2009, p. 6757-6768, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02570-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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