IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase.
Respiratory viral infections increase inflammatory responses to concurrent or secondary bacterial challenges, thereby worsening disease outcome. This potentiation of inflammation is explained at least in part by IFN-gamma promoting increased sensitivity to TNF-alpha and LPS. We sought to determine whether and, if so, how IFN-gamma can modulate proinflammatory responses to TNF-alpha and LPS by epithelial cells, which are key effector cells in the airways. Preincubation of airway epithelial-like NCI-H292 cells with IFN-gamma resulted in a hyperresponsive IL-6 and IL-8 production to TNF-alpha and LPS. The underlying mechanism involved the induction of indoleamine 2,3-dioxygenase, which catabolized the essential amino acid, tryptophan. Depletion of tryptophan led to stabilization of IL-6 and IL-8 mRNA and increased IL-6 and IL-8 responses, whereas supplementing tryptophan largely restored these changes. This novel mechanism may be implicated in enhanced inflammatory responses to bacterial challenges following viral infection.
van Wissen
Matthijs
M
Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Snoek
Mieke
M
Smids
Barbara
B
Jansen
Henk M
HM
Lutter
René
R
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014364:Tryptophan / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014366:Tryptophan Oxygenase / Q000096:biosynthesis / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D000276:Adjuvants, Immunologic; D017077:Culture Media, Conditioned; D006684:HLA-DR Antigens; D007371:Interferon-gamma; D015850:Interleukin-6; D016209:Interleukin-8; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D000093242:Interleukin-6 Inhibitors