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Article
Nature Medicine  6, 422 - 428 (2000)
doi:10.1038/74680

Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway

Leo E. Otterbein1, 3, Fritz H. Bach7, Jawed Alam6, Miguel Soares7, Hong Tao Lu4, Mark Wysk5, Roger J. Davis5, Richard A. Flavell4 & Augustine M.K. Choi1, 2

1  Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06250, USA

2  Connecticut Veterans Affairs, Connecticut Healthcare System, West Haven, Connecticut 06516, USA

3  The Johns Hopkins University, Baltimore, Maryland 21205, USA

4  Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06250, USA

5  Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

6  Department of Molecular Genetics, Alton Ochsner Medical Foundation and Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, Louisiana 70121, USA

7  Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

Correspondence should be addressed to Augustine M.K. Choi augustine.choi@yale.edu
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.

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Nature Medicine
ISSN: 1078-8956
EISSN: 1546-170X
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