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 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.
Bilban
Martin
M
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Bach
Fritz H
FH
Otterbein
Sherrie L
SL
Ifedigbo
Emeka
E
d'Avila
Joana de Costa
JC
Esterbauer
Harald
H
Chin
Beek Yoke
BY
Usheva
Anny
A
Robson
Simon C
SC
Wagner
Oswald
O
Otterbein
Leo E
LE
D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000276:immunology / Q000494:pharmacology*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000187:drug effects / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology / Q000378:metabolism; D055370:Lung Injury; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D047493:PPAR alpha / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D047493:PPAR alpha; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D006899:Mixed Function Oxygenases