Role of p38 mitogen-activated protein kinase in rhinovirus-induced cytokine production by bronchial epithelial cells.
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-alpha), 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 microM. 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.
Griego
S D
SD
Departments of. Molecular Virology and Host Defense and Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426, USA. SandraDGriego@sbphrd.com
Weston
C B
CB
Adams
J L
JL
Tal-Singer
R
R
Dillon
S B
SB
D001980:Bronchi / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010850:Picornaviridae Infections / Q000276:immunology / Q000821:virology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D012229:Rhinovirus / Q000276:immunology* / Q000528:radiation effects; D014443:Tyrosine / Q000378:metabolism; D014466:Ultraviolet Rays; D014775:Virus Activation / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580