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* From the Departments of Pulmonology (Drs. Lutter, Roger, Bresser, and Jansen), Experimental Immunology (Mr. van Wissen), and Experimental Internal Medicine (Mr. van der Sluijs), Academic Medical Center, University of Amsterdam, the Netherlands; and the Department of Virology (Dr. Nijhuis), Eijkman-Winkler Institute, University Medical Center, Utrecht, the Netherlands.
Correspondence to: René Lutter, PhD, Academic Medical Center, Departments of Pulmonology and Experimental Immunology, G1-140, Meibergdreef 9, PO Box 22700, 1100 DE Amsterdam, the Netherlands; e-mail: r.lutter{at}amc.uva.nl
Many of the proteins that we tend to measure in asthma as indicators of airway inflammation (eg, interleukin [IL]-6, IL-8, granulocyte-macrophage colony-stimulating factor, intercellular adhesion molecule-1, c-jun, and c-fos) or of pathophysiology (eg, endothelin-1, ß-adrenergic receptor, glucocorticoid receptor, and inducible nitric oxide synthetase) have in common that their encoding messenger RNA (mRNA) is targeted for rapid degradation. This facilitated degradation ensures that mRNA and, thus, protein expression are limited, which is a crucial regulatory mechanism given that most of these labile mRNAs encode for proteins that can initiate and direct, or redirect, responses. Illustrative in this context is that mice in which the proinflammatory mediator IL-6 was overexpressed in the airway epithelium developed major airway pathology.1 Not surprisingly, therefore, mRNA degradation is strictly regulated, involving complex activation cascades and a range of mRNA-binding proteins.
Our previous studies have focused on the implications of a reduced IL-6 and IL-8 mRNA degradation for IL-6 and IL-8 responses by airway epithelial cells,2 3 4 which are key effector cells in the airways. It has been proposed5 that the degradation of labile mRNAs containing AUUUA sequences in the 3'-untranslated region, as indeed are present in IL-6 and IL-8 mRNA, is dependent on de novo protein synthesis. Indeed, the limitation of protein synthesis by synthetic inhibitors resulted in a markedly prolonged half-life for these mRNAs in airway epithelial cells.2 3 Interestingly, a reduced IL-6 and IL-8 mRNA degradation had profound effects on the dose-response curves (Fig 1 ).4 Cells with a reduced IL-6 and IL-8 mRNA degradation showed the following: (1) a steeper dose-response curve, (2) a lowered threshold concentration for a stimulus to induce IL-6 and IL-8, and (3) prolonged IL-6 and IL-8 production. In other words, cells turned from normal responsive into hyperresponsive cells for IL-6 and IL-8 when IL-6 and IL-8 mRNA degradation were reduced. So far, the human airway epithelial-like cell lines NCI-H292 and Calu-3, as well as primary bronchial epithelial cells, displayed this hyperresponsiveness, but neither primary and cell line fibroblasts or peripheral blood mononuclear cells did, which is suggestive of cell-type specificity.5
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Respiratory viral infections are a major cause of exacerbations in asthma patients.6
These clinical manifestations are paralleled by the recruitment and activation of inflammatory cells, and have led to studies into the role of proinflammatory mediators during a viral infection. Levels of IL-6 and IL-8 are increased in airway secretions from individuals with a respiratory viral infection. Furthermore, the kinetics and magnitude of IL-6 and IL-8 were found to correlate with respiratory symptoms in influenza infection, thus underlining the prominent role of these mediators in virus-induced pathophysiology. Interferon (IFN)-
is generated during viral infection and is considered to be a major modulator of innate immune responses.7
We sought to determine whether and, if so, how IFN- modulates IL-6 and IL-8 responses to proinflammatory stimuli (eg, tumor necrosis factor [TNF]-
and lipopolysaccharide [LPS]) by epithelial cells. In addition, we assessed whether IL-6 and IL-8 responses are modulated in virus-infected NCI-H292 airway-derived epithelial cells.
NCI-H292 cells that were preexposed to IFN- (100 U/mL) for 24 h subsequently displayed exaggerated IL-6 and IL-8 responses to TNF- and LPS. The underlying mechanism involved the induction of the enzyme indolamine 2,3-dioxygenase, which via depletion of tryptophan reduced protein synthesis and IL-6 and IL-8 mRNA degradation. The addition of exogenous tryptophan largely reversed the reduced mRNA degradation and the exaggerated IL-6 and IL-8 responses.8
Parainfluenza virus type 4, which is a member of the pathogenic Paramyxoviruses but in contrast to other members is less cytopathic, was used to assess whether virus-infected cells display a change in the regulation of the IL-6 and IL-8 responses. With time, virus-infected cells displayed a phase with exaggerated IL-6 and IL-8 responses to a secondary stimulus, as exemplified by steeper dose-response curves. This phase also coincided with a marked reduction of IL-6 and IL-8 mRNA degradation (Roger et al; unpublished data). Whether this is due to a reduced protein synthesis remains to be shown.
We propose that during a respiratory viral infection, conditions can occur that reduce epithelial IL-6 and IL-8 mRNA degradation, which will lead to exaggerated proinflammatory responses. These in vitro findings await confirmation in in vivo settings. Whether similar exaggerated responses occur for other proteins encoded by a labile mRNA is unknown.
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Acknowledgements |
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This research was supported by a European Union grant (contract ERBCHBGCT940673), by the Netherlands Asthma Foundation (grant 97.48), and by Stichting Astma Bestrijding (grant 97/12).
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