Open AccessVaccinia Virus E3 Suppresses Expression of Diverse Cytokines through Inhibition of the PKR, NF-κB, and IRF3 Pathways
Author(s) -
Chad Myskiw,
Janilyn Arsenio,
Rebekah van Bruggen,
Yvon Deschambault,
Jingxin Cao
Publication year - 2009
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.02570-08
Subject(s) - irf3 , biology , protein kinase r , interferon , tumor necrosis factor alpha , interferon regulatory factors , cytokine , vaccinia , eif 2 kinase , virus , signal transduction , nf κb , nfkb1 , virology , microbiology and biotechnology , protein kinase a , immunology , immune system , phosphorylation , transcription factor , innate immune system , gene , genetics , recombinant dna , mitogen activated protein kinase kinase , protein kinase c , cyclin dependent kinase 2
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-α). 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-α, 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-κB was required for vaccinia virus-induced INHBA expression, whereas induction of TNF-α required only PKR-dependent NF-κB activation. In contrast, induction of IL-6 and IFN-β was largely PKR independent. IL-6 induction is regulated by NF-κB, while IFN-β induction is mediated by IFN-β promoter stimulator 1 and IFN regulatory factor 3/NF-κB. Collectively, these results indicate that E3 suppresses distinct but interlinked host signaling pathways to inhibit the expression of a diverse array of cytokines.