MAPK activation is involved in posttranscriptional regulation of RSV-induced RANTES gene expression

• Published in: American journal of physiology. Lung cellular and molecular physiology 2002-08, Vol.283 (2), p.364-L372
• Main Authors: Pazdrak, Konrad, Olszewska-Pazdrak, Barbara, Liu, Tianshuang, Takizawa, Ryuta, Brasier, Allan R, Garofalo, Roberto P, Casola, Antonella
• Format: Article
• Language: English
• Subjects: Bronchi - cytology; Bronchi - metabolism; Cell Line; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Enzyme Activation - physiology; Epithelial Cells - metabolism; Gene Expression Regulation - physiology; Humans; MAP Kinase Kinase Kinase 1; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Pulmonary Alveoli - cytology; Pulmonary Alveoli - metabolism; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - virology; Respiratory Syncytial Viruses - physiology; Virus Replication
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00331.2001

Departments of 1  Pediatrics, 2  Internal Medicine, and 4  Microbiology and Immunology and 3  Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, Texas 77555 Airway epithelial cells represent the primary cell target of respiratory syncytial virus (RSV) infection. They actively participate in the lung immune/inflammatory response that follows RSV infection by expressing chemokines, small chemotactic cytokines that recruit and activate leukocytes. Regulated on activation, normal T cell expressed, and presumably secreted (RANTES) is a member of the CC chemokine subfamily and is strongly chemotactic for T lymphocytes, monocytes, basophils, and eosinophils, cell types that are present or activated in the inflammatory infiltrate that follows RSV infection of the lung. RSV infection of airway epithelial cells induces RANTES expression by increasing gene transcription and stabilizing RNA transcripts. The signaling pathway regulating RANTES gene expression after RSV infection has not been determined. In this study, we examined the role of extracellular signal-regulated kinase (ERK) and p38, members of the mitogen-activated protein (MAP) kinase (MAPK) family, in RSV-induced RANTES production. RSV infection of alveolar epithelial cells induced increased phosphorylation and catalytic activity of ERK and the upstream kinases Raf-1 and MAP ERK kinase. Induction of the MAP signaling cascade required a replication-competent virus. RSV infection of alveolar epithelial cells also induced activation of p38 MAPK. Inhibition of ERK and p38 activation significantly reduced RSV-induced RANTES mRNA and protein secretion without affecting RANTES gene transcription or transcription factor activation. These results indicate that the MAPK signaling cascade regulates RANTES production in alveolar epithelial cells through a posttranscriptional mechanism. respiratory syncytial virus; chemokine; signal transduction; gene regulation; mitogen-activated protein kinase; regulated on activation; normal T cell expressed, and presumably secreted