Exaggerated IL-8 and IL-6 responses to TNF-alpha by parainfluenza virus type 4-infected NCI-H292 cells.
Respiratory viruses induce and potentiate airway inflammation, which is related to the induction of proinflammatory mediators such as interleukin (IL)-8 and IL-6. Here we report on mechanisms implicated in IL-8 and IL-6 production by airway epithelium-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-kappaB and activator protein (AP)-1, and CCAAT-enhancer binding protein (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-kappaB 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-alpha. Thus PIV-4 infection enhances epithelial IL-8 and IL-6 production by transcriptional and posttranscriptional 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 virus-induced potentiation of airway inflammation.
Department of Pulmonology, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
Thierry
T
Roger
Paul
P
Bresser
Mieke
M
Snoek
Koen
K
van der Sluijs
Arjen
A
van den Berg
Monique
M
Nijhuis
Henk M
HM
Jansen
René
R
Lutter
D000230:Adenocarcinoma; D000970:Antineoplastic Agents / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D018277:Carcinoma, Mucoepidermoid; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms; D016328:NF-kappa B / Q000378:metabolism; D029482:Parainfluenza Virus 4, Human; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D019351:Rubulavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha