Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
-
Carbon Monoxide / pharmacology*
-
Cell Line
-
Cells, Cultured
-
Chemokine CCL4
-
Cyclic GMP / metabolism
-
Enzyme Activation
-
Gene Expression
-
Heme Oxygenase (Decyclizing) / genetics
-
Heme Oxygenase-1
-
Humans
-
Interferon-gamma / biosynthesis
-
Interleukin-1 / biosynthesis
-
Interleukin-10 / genetics
-
Interleukin-10 / metabolism
-
Lipopolysaccharides / pharmacology
-
MAP Kinase Kinase 3
-
MAP Kinase Signaling System*
-
Macrophage Inflammatory Proteins / biosynthesis
-
Macrophages, Peritoneal / cytology
-
Macrophages, Peritoneal / drug effects
-
Macrophages, Peritoneal / metabolism
-
Male
-
Membrane Proteins
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mitogen-Activated Protein Kinase Kinases / genetics
-
Mitogen-Activated Protein Kinase Kinases / metabolism*
-
Mitogens / pharmacology
-
Nitric Oxide / metabolism
-
Protein-Tyrosine Kinases / genetics
-
Protein-Tyrosine Kinases / metabolism*
-
RNA Processing, Post-Transcriptional
-
Rats
-
Rats, Sprague-Dawley
-
Tumor Necrosis Factor-alpha / biosynthesis
-
Tumor Necrosis Factor-alpha / genetics
Substances
-
Anti-Inflammatory Agents, Non-Steroidal
-
Chemokine CCL4
-
Interleukin-1
-
Lipopolysaccharides
-
Macrophage Inflammatory Proteins
-
Membrane Proteins
-
Mitogens
-
Tumor Necrosis Factor-alpha
-
Interleukin-10
-
Nitric Oxide
-
Carbon Monoxide
-
Interferon-gamma
-
HMOX1 protein, human
-
Heme Oxygenase (Decyclizing)
-
Heme Oxygenase-1
-
Hmox1 protein, mouse
-
Protein-Tyrosine Kinases
-
MAP Kinase Kinase 3
-
MAP2K3 protein, human
-
Map2k3 protein, mouse
-
Mitogen-Activated Protein Kinase Kinases
-
Cyclic GMP