© 2003 American Thoracic Society DOI: 10.1165/rcmb.4881 Downregulation of the Epidermal Growth Factor Receptor by Human Cytomegalovirus Infection in Human Fetal Lung FibroblastsInstitutes of Virology and Medical Immunology, and Department of Neonatology, University Hospital Charité, Humboldt University, Berlin, Germany Address correspondence to: Dr. Susanna Prösch, Ph.D., Institute of Virology, Univ. Hospital Charité, Humboldt University, Schumannstraße 20/21, D-10117 Berlin, Germany. E-mail: susanna.proesch{at}charite.de Epidermal growth factor plays a key role in late fetal lung development and differentiation as well as in regulating surfactant protein A synthesis, which is involved in innate immunity of the lung. Here we show that human cytomegalovirus (HCMV), a known lung pathogen in connatal and postnatal infection of neonates as well as transplant recipients, completely down-regulates EGF receptor (EGF-R) on the surface of human fetal lung fibroblasts. Inhibition of EGF-R synthesis occurs on the transcriptional rather than on the posttranscriptional level. The effect essentially depends on expression of viral immediate early and/or early genes, as binding of ultraviolet light-inactivated virus to the cells had no effect on EGF-R expression. Furthermore, the anti-HCMV drug ganciclovir, which blocks HCMV DNA replication and late gene expression, cannot overcome HCMV-mediated inhibition of EGF-R, suggesting that immediate early or early gene products may be responsible for down-regulation of EGF-R. Interestingly, the glucocorticoid dexamethasone, which is used for its antiinflammatory action to prevent chronic lung disease in preterm infants, promotes HCMV-associated downregulation of the EGF-R by stimulation of viral gene expression. From these data it can be hypothesized that the pathogenesis of HCMV lung infection involves down-regulation of EGF-R and that congenital HCMV infection may cause retardation in lung maturation and surfactant protein synthesis.
Abbreviations: bronchopulmonary dysplasia, BPD • chemiluminescence detection system, CCD • cycloheximide, CHX • dexamethasone, Dexa • epidermal growth factor, EGF • fluorescence-activated cell sorter, FACS • fetal calf serum, FCS • ganciclovir, GCV • human cytomegalovirus, HCMV • human fetal lung fibroblasts, HFLF • horseradish peroxidase, HRP • immediate early, IE • immunoglobulin, Ig • multiplicity of infection, MOI • messenger RNA, mRNA • phosphate buffered saline, PBS • phycoerythrin, PE • phenyl-methyl-sulfonyl fluoride, PMSF • sodium dodecyl sulfate, SDS • surfactant protein A, SP-A • TBST • tumor growth factor, TGF • ultraviolet light, UV This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||
