Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology*
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Culture Media, Conditioned / metabolism
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Dose-Response Relationship, Immunologic
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HLA-DR Antigens / biosynthesis
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HLA-DR Antigens / metabolism
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Humans
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Interferon-gamma / pharmacology*
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / biosynthesis*
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Interleukin-6 / genetics
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / biosynthesis*
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Interleukin-8 / genetics
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / metabolism
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Respiratory Mucosa / enzymology
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Respiratory Mucosa / immunology*
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Respiratory Mucosa / metabolism*
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Tryptophan / antagonists & inhibitors
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Tryptophan / metabolism
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Tryptophan / physiology
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Tryptophan Oxygenase / biosynthesis
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Tryptophan Oxygenase / physiology*
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Tumor Cells, Cultured
Substances
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Adjuvants, Immunologic
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Culture Media, Conditioned
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HLA-DR Antigens
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Interleukin-6
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Interleukin-8
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Protein Synthesis Inhibitors
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RNA, Messenger
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Interferon-gamma
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Tryptophan
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Tryptophan Oxygenase