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IB Kinase Is a Critical Regulator of Chemokine Expression and Lung Inflammation in Respiratory Syncytial Virus Infection

Helene A. Haeberle,^1,2 Antonella Casola,^1,3,4 Zoran Gatalica,^5, Sharon Petronella,¹ Hans-Juergen Dieterich,² Peter B. Ernst,^1, Allan R. Brasier,⁶ and Roberto P. Garofalo^1,3,4*

Departments of Pediatrics,¹ Pathology,⁵ Medicine,⁶ Microbiology and Immunology,³ Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas,⁴ Department of Anesthesiology, Universitaetsklinikum, Tuebingen, Germany²

Received 18 October 2002/ Accepted 28 October 2003

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 IB kinase (IKK) in lung tissue. IKK transduces upstream activating signals into the rate-limiting phosphorylation (and proteolytic degradation) of IB, the inhibitory subunit that under normal conditions binds to the nuclear factor (NF)-B 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 IKKß with the regulatory protein NEMO showed a striking reduction of lung NF-B DNA binding activity, chemokine gene expression, and airway inflammation in response to RSV infection. These findings suggest that IKKß may be a potential target for the treatment of acute or chronic inflammatory diseases of the lung.

Present address: Department of Anatomic Pathology, Creighton University Medical Center, Omaha, Nebr.

Present address: Department of Internal Medicine, University of Virginia, Charlottesville, Va.

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