RHINOVIRUS STIMULATION OF INTERLEUKIN-8 IN-VIVO AND IN-VITRO - ROLE OF NF-KAPPA-B

Neutrophil infiltration is a well-documented early event in the pathog enesis of rhinovirus (RV) infections. To further understand the mechan isms responsible for this neutrophilia, we determined whether interleu kin (IL)-8 was present at sites of experimental RV infection in vivo a nd characterized the mechanism(s) by which RV stimulates IL-8 producti on 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 na sal 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 epitheli al-like cells, MRC-5 fibroblasts, and normal human bronchial epithelia l cells in vitro. This induction was associated with a significant inc rease in IL-8 mRNA accumulation and gene transcription. RV also stimul ated IL-8 promoter-driven luciferase activity. This stimulation was si gnificantly decreased by mutation of the nuclear factor (NF)-IL-6 site and was completely abrogated by mutation of the NF-kappa B site in th is promoter. In addition, NF-kappa B-DNA binding activity was rapidly induced in RV-infected cells. This inducible binding was made up of p6 5 and, to a lesser extent, p50 NF-kappa B moieties. These studies demo nstrate that IL-8 is present in normal nasal secretions and that the l evels of IL-8 are further increased after RV infection. They also demo nstrate that RVs are potent stimulators of IL-8 production and that th is induction is mediated, at least in part, by an NF-kappa B-dependent transcriptional activation pathway. IL-8 may contribute to the pathog enesis of RV infection, and NF-kappa B activation may be a central eve nt in RV-induced pathologies.