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by parainfluenza virus type 4-infected NCI-H292 cells
1 Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2 Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3 Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
4 Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
5 Virology, Eijkman-Winkler Institute, Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: r.lutter{at}amc.uva.nl.
Respiratory viruses induce and potentiate airway inflammation, which is related to the induction of pro-inflammatory mediators such as interleukin (IL)-8 and IL-6. Here we report on mechanisms implicated in IL-8 and IL-6 production by airway epithelial-like NCI-H292 cells exposed to parainfluenza virus type 4a (PIV 4). PIV 4 readily infected NCI-H292 cells as reflected by intracellular PIV 4-antigen expression. PIV 4 infection triggered a biphasic IL-8 and IL-6 mRNA response. Transient transfection with truncated and mutated promoter constructs identified NF-
B and AP-1, and C/EBP, as the relevant transcription factors for PIV 4-induced IL-8 and IL-6 gene transcription, respectively. An increase of DNA-binding activities for NF-B and C/EBP paralleled the induction of the first and second IL-8 and IL-6 mRNA peaks, whereas the onset of AP-1 paralleled the first IL-8 mRNA peak only. The second mRNA peak, apparently dependent on viral replication, coincided also with a marked reduction of IL-8 and IL-6 mRNA degradation. Importantly, cells at the time of the reduced mRNA degradation displayed an exaggerated IL-8 and IL-6 protein production to a secondary stimulus, as exemplified by steeper dose response curves to TNF-
. Thus, PIV 4 infection enhances epithelial IL-8 and IL-6 production by transcriptional and post-transcriptional mechanisms. The previously unrecognized phase of reduced IL-8 and IL-6 mRNA degradation and the concurrent amplified epithelial IL-8 and IL-6 responses may play an important role in viral-induced potentiation of airway inflammation.
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