Inhibition of interleukin-6 expression by the V protein of parainfluenza virus 5.
The V protein of parainfluenza virus 5 (PIV5) plays an important role in the evasion of host immune responses. The V protein blocks interferon (IFN) signaling in human cells by causing degradation of the STAT1 protein, a key component of IFN signaling, and blocks IFN-beta production by preventing nuclear translocation of IRF3, a key transcription factor for activating IFN-beta promoter. Interleukin-6 (IL-6), along with tumor necrosis factor (TNF)-alpha and IL-1beta, is a major proinflammatory cytokine that plays important roles in clearing virus infection through inflammatory responses. Many viruses have developed strategies to block IL-6 expression. Wild-type PIV5 infection induces little, if any, expression of cytokines such as IL-6 or TNF-alpha, whereas infection by a mutant PIV5 lacking the conserved C-terminal cysteine rich domain (rPIV5VDeltaC) induced high levels of IL-6 expression. Examination of mRNA levels of IL-6 indicated that the transcription activation of IL-6 played an important role in the increased IL-6 expression. Co-infection with wild-type PIV5 prevented the activation of IL-6 transcription by rPIV5VDeltaC, and a plasmid encoding the full-length PIV5 V protein prevented the activation of IL-6 promoter-driven reporter gene expression by rPIV5VDeltaC, indicating that the V protein played a role in inhibiting IL-6 transcription. The activation of IL-6 was independent of IFN-beta even though rPIV5VDeltaC-infected cells produced IFN-beta. Using reporter gene assays and chromatin immunoprecipitation (ChIP), it was found that NF-kappaB played an important role in activating expression of IL-6. We have proposed a model of activating and inhibiting IL-6 transcription by PIV5.
Lin
Yuan
Y
Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Sun
Minghao
M
Fuentes
Sandra M
SM
Keim
Celia D
CD
Rothermel
Terri
T
He
Biao
B
D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D045402:Parainfluenza Virus 5 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D015850:Interleukin-6; D016328:NF-kappa B; C097019:V protein, Simian parainfluenza virus 5; D015678:Viral Structural Proteins
Vet Rec. 1978 Apr 8;102(14):293-301
207006
J Gen Virol. 2004 Oct;85(Pt 10):3007-16
15448364
Cell. 1988 Sep 9;54(6):891-902
3044614
EMBO J. 1990 Jun;9(6):1897-906
2112087
Gene. 1991 Dec 15;108(2):193-9
1660837
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455-9
1837150
Virology. 1994 Jan;198(1):399-404
8259680
Mol Cell Biol. 1994 Nov;14(11):7377-84
7935451
Arch Virol. 1995;140(7):1321-8
7646364
Virology. 1996 Oct 1;224(1):121-9
8862406
Virology. 1997 Nov 24;238(2):460-9
9400618
J Biol Chem. 1998 Feb 6;273(6):3285-90
9452444
Annu Rev Immunol. 1998;16:225-60
9597130
Genes Dev. 1998 Jul 1;12(13):2061-72
9649509
Virology. 1998 Sep 15;249(1):189-200
9740790
Virology. 1998 Oct 10;250(1):30-40
9770417
Mol Cell Biol. 1999 Feb;19(2):959-66
9891032
J Biol Chem. 1999 Apr 16;274(16):10689-92
10196138
J Virol. 1999 Oct;73(10):8703-12
10482624
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17264-9
15563593
J Virol. 2005 Jan;79(1):472-85
15596840
Virology. 2005 Aug 1;338(2):270-80
15950997
Clin Rev Allergy Immunol. 2005 Jun;28(3):177-86
16129902
J Immunol. 2005 Sep 15;175(6):3463-8
16148087
J Virol. 2005 Nov;79(21):13434-41
16227264
J Virol. 2006 Jan;80(2):866-74
16378988
J Virol. 2006 Feb;80(4):1700-9
16439527
J Virol. 2006 Apr;80(7):3416-27
16537609
Virology. 2006 Jun 20;350(1):90-102
16480754
J Virol. 2007 Aug;81(15):8361-6
17494063
J Biol Chem. 1999 Nov 5;274(45):32091-8
10542243
J Virol. 1999 Dec;73(12):9928-33
10559305
J Virol. 2000 Oct;74(19):9152-66
10982362
J Virol. 2001 May;75(9):4068-79
11287556
Blood. 2002 Jan 15;99(2):649-54
11781250
Virology. 1995 Apr 1;208(1):121-31
11831692
J Virol. 2002 Apr;76(8):3952-64
11907235
J Virol. 2002 May;76(9):4190-8
11932384
Nat Rev Cancer. 2002 Apr;2(4):301-10
12001991
Infect Immun. 2002 Jul;70(7):3311-7
12065467
J Virol. 2002 Sep;76(18):9284-97
12186912
J Virol. 2002 Nov;76(22):11379-86
12388698
Virology. 2002 Nov 10;303(1):15-32
12482655
Virology. 2002 Nov 10;303(1):33-46
12482656
Virology. 2002 Dec 20;304(2):160-6
12504558
J Virol. 2003 Mar;77(6):3371-83
12610112
J Virol. 2003 Jul;77(14):7903-13
12829830
J Virol. 2004 May;78(10):5068-78
15113888
J Virol. 1988 Jul;62(7):2347-57
2836617