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

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 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 IKK␤ 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 IKK␤ may be a potential target for the treatment of acute or chronic inflammatory diseases of the lung.Respiratory syncytial virus (RSV), a single-stranded negativesense RNA virus of the Paramyxoviridae family, is well recognized as the major cause of serious lower respiratory disease in infancy and early childhood as well as in the elderly. In bronchiolitis, the most severe clinical manifestation of RSV infection, an intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs concomitantly with considerable edema, sloughing of the respiratory epithelium, and plugging of the small bronchioles with fibrin and mucus (1,8).Chemokines, a superfamily of small, structurally related molecules, induce the migration and activation of leukocytes and have emerged as central regulatory molecules in inflammatory, immune, and infectious processes of the lung (29). Indirect evidence suggests that these inflammatory molecules may play a critical role in the pathogenesis of RSV disease in infants. We recently reported that in the BALB/c mouse model, which shows close similarity to the pathogenesis of RSV-induced lower airway disease in humans, intranasal (i.n.) infection with RSV results in the rapid inducible expression of lung chemokines belonging to the CXC, CC, and C families. The levels of chemokines were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Furthermore, genetically altered mice with a selective deletion of the chemokine MIP-1␣ gene (Ϫ/Ϫ) had a significant reduction in lung inflammation following RSV infection compared to control (ϩ/ϩ) littermates (14).Studies in vitro and in vivo have also demonstrated that RSV is among the most potent biological stimuli that are able to induce chemokine and cytokine p...

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SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

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