Carbon monoxide orchestrates a protective response through PPARgamma

Carbon monoxide (CO) suppresses proinflammatory responses in macrophages reacting to LPS. We hypothesize that CO acts by inducing a molecule(s) that suppresses the inflammatory response to subsequent stress. Exposure of macrophages to CO alone in vitro produced a brief burst of mitochondrial-derived...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2006-05, Vol.24 (5), p.601-610
Main Authors: Bilban, Martin, Bach, Fritz H, Otterbein, Sherrie L, Ifedigbo, Emeka, d'Avila, Joana de Costa, Esterbauer, Harald, Chin, Beek Yoke, Usheva, Anny, Robson, Simon C, Wagner, Oswald, Otterbein, Leo E
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Carbon Monoxide - immunology
Carbon Monoxide - pharmacology
Disease Models, Animal
Early Growth Response Protein 1 - drug effects
Early Growth Response Protein 1 - immunology
Electrophoresis, Polyacrylamide Gel
Electrophoretic Mobility Shift Assay
Gene Expression - drug effects
Inflammation - immunology
Inflammation - prevention & control
Lung - drug effects
Lung - pathology
Lung Diseases - immunology
Lung Diseases - metabolism
Lung Injury
Macrophages - drug effects
Macrophages - immunology
Mice
Mitochondria - drug effects
Mixed Function Oxygenases - drug effects
Oxidative Stress - drug effects
Oxidative Stress - immunology
PPAR alpha - drug effects
PPAR alpha - immunology
PPAR alpha - metabolism
Reactive Oxygen Species - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - analysis
Transfection
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Summary:Carbon monoxide (CO) suppresses proinflammatory responses in macrophages reacting to LPS. We hypothesize that CO acts by inducing a molecule(s) that suppresses the inflammatory response to subsequent stress. Exposure of macrophages to CO alone in vitro produced a brief burst of mitochondrial-derived ROS, which led to expression of PPARgamma. PPARgamma expression proved essential for mediating the anti-inflammatory effects of CO. Blocking the CO-mediated increase in ROS generation prevented PPARgamma induction, and blocking PPARgamma prevented CO's anti-inflammatory effects. In a model of acute lung injury in mice, CO blocked expression of Egr-1, a central mediator of inflammation, and decreased tissue damage; inhibition of PPARgamma abrogated both effects. These data identify the mitochondrial oxidases as an (perhaps the) initial cellular target of CO and demonstrate that CO upregulates expression of PPARgamma via the mitochondria, which assures that a subsequent stress stimulus will lead to a cytoprotective as opposed to a proinflammatory phenotype.
ISSN:1074-7613