Role of p38 Mitogen-Activated Protein Kinase in Rhinovirus-Induced Cytokine Production by Bronchial Epithelial Cells

Abstract

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-α), 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.

Immunomodulation of Nasal Epithelial Cells by Staphylococcus aureus-Derived Serine Proteases

“…To confirm these observations and to elucidate the impact of cell signaling on cytokine synthesis in our model, cell signaling inhibition experiments have been performed using MAPK inhibitors PD98059, wortmannin, and SB-239063 (15). From these experiments, we learned that particularly PI3K plays a role in the transduction pathway triggered by S. aureus hemB mutants and trypsin for gene transcription of IL-8.…”

“…MAPKs were inhibited by pretreatment with either PD98059 (Calbiochem) at a concentration of 50 M and wortmannin (Calbiochem) at a concentration of 100 nM or the selective p38 inhibitor SB-239063 (trans-1-(4 hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole) at a concentration of 30 M, 30 min before challenge with bacterial supernatants (BioSource International) (15).…”

Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK

“…Treatment with p38 kinase inhibitor (SB203580) shows a suppressed production of inflammatory mediators such as TNF, IL-1, IL-6, CXCL8/IL-8, and GM-CSF (14). p38 kinase is essential for virus-induced cytokine production by bronchial epithelial cells including IL-6, IL-8, and GM-CSF (15)(16)(17). We have shown that p38 kinase is involved in the hyperinduction of TNF-␣ expression in H5N1-infected macrophages (18), although the mechanisms underlying this hyperinduction of cytokine by H5N1 influenza virus have not been elucidated.…”

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

“…Rhinovirus infection of the bronchial epithelium induces expression of numerous proinflammatory genes (55)(56)(57)(58). Induction of nuclear factor (NF)-kB and other transcription factors has been clearly demonstrated with several viruses including HRV, RSV, and influenza (59)(60)(61)(62)(63)(64).…”