Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.
The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.
Otterbein
L E
LE
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06250, USA.
Bach
F H
FH
Alam
J
J
Soares
M
M
Tao Lu
H
H
Wysk
M
M
Davis
R J
RJ
Flavell
R A
RA
Choi
A M
AM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D054407:Chemokine CCL4; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D020935:MAP Kinase Signaling System; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054407:Chemokine CCL4; D007375:Interleukin-1; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D008934:Mitogens; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D002248:Carbon Monoxide; D007371:Interferon-gamma; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D011505:Protein-Tyrosine Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D006152:Cyclic GMP