Rhinovirus stimulation of interleukin-8 in vivo and in vitro: role of NF-kappaB.
Neutrophil infiltration is a well-documented early event in the pathogenesis of rhinovirus (RV) infections. To further understand the mechanisms responsible for this neutrophilia, we determined whether interleukin (IL)-8 was present at sites of experimental RV infection in vivo and characterized the mechanism(s) by which RV stimulates IL-8 production in vitro. IL-8 was readily detectable in the nasal washings of all normal volunteers and did not increase with sham nasal inoculation. In contrast, RV infection caused a significant additional increase in nasal IL-8, the levels of which peaked 48-72 h after virus inoculation. RV was a potent stimulator of IL-8 protein production by A549 epithelial-like cells, MRC-5 fibroblasts, and normal human bronchial epithelial cells in vitro. This induction was associated with a significant increase in IL-8 mRNA accumulation and gene transcription. RV also stimulated IL-8 promoter-driven luciferase activity. This stimulation was significantly decreased by mutation of the nuclear factor (NF)-IL-6 site and was completely abrogated by mutation of the NF-kappaB site in this promoter. In addition, NF-kappaB-DNA binding activity was rapidly induced in RV-infected cells. This inducible binding was made up of p65 and, to a lesser extent, p50 NF-kappaB moieties. These studies demonstrate that IL-8 is present in normal nasal secretions and that the levels of IL-8 are further increased after RV infection. They also demonstrate that RVs are potent stimulators of IL-8 production and that this induction is mediated, at least in part, by an NF-kappaB-dependent transcriptional activation pathway. IL-8 may contribute to the pathogenesis of RV infection, and NF-kappaB activation may be a central event in RV-induced pathologies.
Zhu
Z
Z
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Tang
W
W
Gwaltney
J M
JM
Wu
Y
Y
Elias
J A
JA
D000328:Adult; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003139:Common Cold / Q000276:immunology*; D004847:Epithelial Cells; D005347:Fibroblasts; D017930:Genes, Reporter; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008156:Luciferases / Q000096:biosynthesis; D008168:Lung; D016328:NF-kappa B / Q000378:metabolism*; D009297:Nasal Mucosa / Q000276:immunology / Q000821:virology*; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012229:Rhinovirus / Q000276:immunology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D016209:Interleukin-8; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D008156:Luciferases