Abstract
Respiratory syncytial virus (RSV) is the major etiologic agent of severe epidemic lower respiratory tract infections in infancy. Airway mucosal inflammation plays a critical role in the pathogenesis of RSV disease in both natural and experimental infections. RSV is among the most potent biological stimuli that induce the expression of inflammatory genes, including those encoding chemokines, but the mechanism(s) that controls virus-mediated airway inflammation in vivo has not been fully elucidated. Herein we show that the inoculation of BALB/c mice with RSV results in rapid activation of the multisubunit IkappaB kinase (IKK) in lung tissue. IKK transduces upstream activating signals into the rate-limiting phosphorylation (and proteolytic degradation) of IkappaBalpha, the inhibitory subunit that under normal conditions binds to the nuclear factor (NF)-kappaB complex and keeps it in an inactive cytoplasmic form. Mice treated intranasally with interleukin-10 or with a specific cell-permeable peptide that blocks the association of the catalytic subunit IKKbeta with the regulatory protein NEMO showed a striking reduction of lung NF-kappaB DNA binding activity, chemokine gene expression, and airway inflammation in response to RSV infection. These findings suggest that IKKbeta may be a potential target for the treatment of acute or chronic inflammatory diseases of the lung.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bronchoalveolar Lavage
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Cell Line, Tumor
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Chemokine CCL2 / biosynthesis
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Chemokine CCL2 / genetics
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Chemokine CCL4
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Chemokine CCL5 / biosynthesis
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Chemokine CCL5 / genetics
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Chemokines / biosynthesis*
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Chemokines / genetics
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Female
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Humans
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I-kappa B Kinase
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Interleukin-10 / pharmacology
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Lung / metabolism
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Lung / virology
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Macrophage Inflammatory Proteins / biosynthesis
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Macrophage Inflammatory Proteins / genetics
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Mice
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Mice, Inbred BALB C
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Peptides / pharmacology
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Pneumonia / enzymology
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Pneumonia / metabolism*
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Pneumonia / pathology
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Pneumonia / virology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Respiratory Syncytial Virus Infections / enzymology
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Respiratory Syncytial Virus Infections / metabolism*
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Respiratory Syncytial Virus Infections / pathology*
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Respiratory Syncytial Viruses / physiology
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Virus Replication
Substances
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Chemokine CCL2
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Chemokine CCL4
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Chemokine CCL5
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Chemokines
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Macrophage Inflammatory Proteins
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NF-kappa B
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Peptides
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RNA, Messenger
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Interleukin-10
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse