Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages.
The stress-inducible gene heme oxygenase-1 (HO-1) provides protection against oxidative stress. Although the mechanisms by which HO-1 exerts its cytoprotection are not clearly understood, it has been speculated that carbon monoxide (CO), a catalytic byproduct following heme catabolism by HO-1, may mediate cellular cytoprotection via its anti-inflammatory properties. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a potent cytokine generated in response to bacterial endotoxin (lipopolysaccharide [LPS]) to stimulate proliferation, maturation, and effector functions of leukocytes, contributing to the proinflammatory responses to LPS. We hypothesized that HO-1 and/or CO could regulate the expression and production of GM-CSF. HO-1 overexpression, as well as exposure to a low concentration of CO, inhibited LPS-induced GM-CSF production in macrophages. Furthermore, CO inhibited LPS-induced GM-CSF induction via inhibition in the activation of the transcription factor NF-kappaB. CO inhibited LPS-induced activation of NF-kappaB, which has been shown to regulate GM-CSF transcription, by preventing the phosphorylation and degradation of the regulatory subunit IkappaB-alpha. These data raise the intriguing possibility that CO at low concentrations may play an important role in inflammatory disease states and thus has potential therapeutic implications.
Sarady
Judit K
JK
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Otterbein
Sherrie L
SL
Liu
Fang
F
Otterbein
Leo E
LE
Choi
Augustine M K
AM
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015854:Up-Regulation / Q000187:drug effects
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D002248:Carbon Monoxide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse