Defining critical roles for NF-?B p65 and type I interferon in innate immunity to rhinovirus

被引:67
作者
Bartlett, Nathan W. [1 ,2 ,3 ,4 ]
Slater, Louise [1 ,2 ,3 ,4 ]
Glanville, Nicholas [1 ,2 ,3 ,4 ]
Haas, Jennifer J. [1 ,2 ,3 ,4 ]
Caramori, Gaetano [5 ]
Casolari, Paolo [5 ]
Clarke, Deborah L. [4 ,6 ]
Message, Simon D. [1 ,2 ,3 ,4 ,7 ]
Aniscenko, Julia [1 ,2 ,3 ,4 ]
Kebadze, Tatiana [1 ,2 ,3 ,4 ]
Zhu, Jie [1 ,2 ,3 ,4 ]
Mallia, Patrick [1 ,2 ,3 ,4 ,7 ]
Mizgerd, Joseph P. [8 ]
Belvisi, Maria [4 ,6 ]
Papi, Alberto [5 ]
Kotenko, Sergei V. [9 ]
Johnston, Sebastian L. [1 ,2 ,3 ,4 ,7 ]
Edwards, Michael R. [1 ,2 ,3 ,4 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Natl Heart Lung Inst, Dept Resp Med, London, England
[2] MRC, London, England
[3] Asthma UK Ctr Allerg Mech Asthma, London, England
[4] Univ London Imperial Coll Sci Technol & Med, Ctr Resp Infect, London, England
[5] Univ Ferrara, Sez Malattie Apparato Resp, Ctr Studio Malattie Infiammatorie Cron Vie Aeree, I-44100 Ferrara, Italy
[6] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England
[7] Imperial Coll Healthcare Natl Hlth Serv Trust, London, England
[8] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA
[9] UMDNJ New Jersey Med Sch, Univ Hosp Canc Ctr, Dept Biochem & Mol Biol, Newark, NJ USA
基金
英国惠康基金;
关键词
asthma; inflammation; interferon; NF-kappaB; rhinovirus; BRONCHIAL EPITHELIAL-CELLS; DOUBLE-STRANDED-RNA; FACTOR-KAPPA-B; THYMIC STROMAL LYMPHOPOIETIN; ALLERGIC AIRWAY INFLAMMATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; ASTHMA EXACERBATIONS; VIRAL-INFECTIONS; VIRUS INDUCTION;
D O I
10.1002/emmm.201201650
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The importance of NF-?B activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-?B p65 nuclear expression, NF-?B p65 DNA binding in lung tissue and NF-?B-regulated airway inflammation. In vitro inhibition of NF-?B reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-?B p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1-/- mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-?B p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases. See accompanying article http://dx.doi.org/10.1002/emmm.201202032
引用
收藏
页码:1244 / 1260
页数:17
相关论文
共 64 条
  • [1] Virus infection induces NF-κB-dependent interchromosomal associations mediating monoallelic IFN-β gene expression
    Apostolou, Effie
    Thanos, Dimitris
    [J]. CELL, 2008, 134 (01) : 85 - 96
  • [2] Defining Emerging Roles for NF-κB in Antivirus Responses: Revisiting the Interferon-β Enhanceosome Paradigm
    Balachandran, Siddharth
    Beg, Amer A.
    [J]. PLOS PATHOGENS, 2011, 7 (10)
  • [3] Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation
    Bartlett, Nathan W.
    Walton, Ross P.
    Edwards, Michael R.
    Aniscenko, Juliya
    Caramori, Gaetano
    Zhu, Jie
    Glanville, Nicholas
    Choy, Katherine J.
    Jourdan, Patrick
    Burnet, Jerome
    Tuthill, Tobias J.
    Pedrick, Michael S.
    Hurle, Michael J.
    Plumpton, Chris
    Sharp, Nigel A.
    Bussell, James N.
    Swallow, Dallas M.
    Schwarze, Jurgen
    Guy, Bruno
    WAlmond, Jeffrey
    Jeffery, Peter K.
    Lloyd, Clare M.
    Papi, Alberto
    Killington, Richard A.
    Rowlands, David J.
    Blair, Edward D.
    Clarke, Neil J.
    Johnston, Sebastian L.
    [J]. NATURE MEDICINE, 2008, 14 (02) : 199 - 204
  • [4] EMBRYONIC LETHALITY AND LIVER DEGENERATION IN MICE LACKING THE RELA COMPONENT OF NF-KAPPA-B
    BEG, AA
    SHA, WC
    BRONSON, RT
    GHOSH, S
    BALTIMORE, D
    [J]. NATURE, 1995, 376 (6536) : 167 - 170
  • [5] The x-ray crystal structure of the NF-κB p50•p65 heterodimer bound to the interferon β-κB site
    Berkowitz, B
    Huang, DB
    Chen-Park, FE
    Sigler, PB
    Ghosh, G
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (27) : 24694 - 24700
  • [6] Iκ-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma
    Birrell, MA
    Hardaker, E
    Wong, S
    McCluskie, K
    Catley, M
    De Alba, J
    Newton, R
    Haj-Yahia, S
    Pun, KT
    Watts, CJ
    Shaw, RJ
    Savage, TJ
    Belvisi, MG
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2005, 172 (08) : 962 - 971
  • [7] Rhinovirus infection and house dust mite exposure synergize in inducing bronchial epithelial cell interleukin-8 release
    Bossios, A.
    Gourgiotis, D.
    Skevaki, C. L.
    Saxoni-Papageorgiou, P.
    Lotvall, J.
    Psarras, S.
    Karpathios, T.
    Constandopoulos, A. G.
    Johnston, S. L.
    Papadopoulos, N. G.
    [J]. CLINICAL AND EXPERIMENTAL ALLERGY, 2008, 38 (10) : 1615 - 1626
  • [8] Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium
    Broide, DH
    Lawrence, T
    Doherty, T
    Cho, JY
    Miller, M
    McElwain, K
    McElwain, S
    Karin, M
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (49) : 17723 - 17728
  • [9] Exogenous IFN-β has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus
    Cakebread, Julie A.
    Xu, Yunhe
    Grainge, Chris
    Kehagia, Valia
    Howarth, Peter H.
    Holgate, Stephen T.
    Davies, Donna E.
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2011, 127 (05) : 1148 - U416
  • [10] Rhinovirus induces airway epithelial gene expression through double-stranded RNA and IFN-dependent pathways
    Chen, Y
    Hamati, E
    Lee, PK
    Lee, WM
    Wachi, S
    Schnurr, D
    Yagi, S
    Dolganov, G
    Boushey, H
    Avila, P
    Wu, R
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2006, 34 (02) : 192 - 203