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Departments of
*
Molecular Virology and Host Defense and
Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426
The stress-activated protein kinase p38 plays a central role in the
regulation of cytokine biosynthesis by various cell types in response
to a wide range of stimuli. Because the local inflammatory response and
the infiltration of neutrophils is thought to contribute to the
symptoms and sequelae of rhinovirus infection, we investigated the role
of p38 kinase in cytokine and chemokine elaboration in airway
epithelial cells infected with human rhinovirus. Rhinovirus-39
infection of BEAS-2B cells resulted in synthesis of cytokines (IL-1,
IL-6, G-CSF, and GM-CSF) and CXC chemokines (IL-8, epithelial
neutrophil-activating protein-78, and growth-related oncogene-
),
evident 24–72 h postinfection. Rhinovirus infection induced a time-
and dose-dependent increase in tyrosine phosphorylation of p38 kinase,
which peaked 30 min postinfection and remained elevated for 1 h.
Treatment of infected cells with SB 239063, a potent pyridinyl
imidazole inhibitor of p38 kinase, resulted in up to 100% inhibition
of mediator production and partially reduced levels of IL-8 mRNA as
determined by quantitative RT-PCR. Treatment with SB 239063 had no
effect on virus replication and was not cytotoxic at
concentrations 
70 µM. These studies provide the first
evidence that early activation of p38 kinase by rhinovirus infection is
a key event in regulation of virus-induced cytokine transcription, and
may provide a new target for inhibition of symptoms and airway
inflammation associated with rhinovirus
infection.
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