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

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-α, interleukin-1β, and macrophage inflammatory protein-1β 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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Figure 1: Effects of overexpression of HO-1 in macrophages on LPS-induced TNF-α production.
Figure 2: Effects of CO on LPS-induced cytokine production in vitro.
Figure 3: CO inhibits LPS-induced production of TNF-α and IL-10.
Figure 4: Effects of CO on LPS-induced activation of MAP kinases.
Figure 5: Effects of CO on LPS-induced serum production of TNF-α and IL-10 in Mkk3−/− mice.
Figure 6: Effect of CO on LPS-induced TNF-α expression.

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Acknowledgements

We thank E. Ifedigbo for his engineering and construction of the carbon monoxide exposure apparatus and S. Otterbein for assisting in preparation and review of the manuscript. The work by A.M.K.C. was supported by National Institutes of Health (NIH) grants HL55330, HL60234, and AI42365 and American Heart Association Established Investigator Award. L.E.O. was supported by the Multidisciplinary Lung Training Grant (National Heart, Lung and Blood Institute). J.A. was supported by NIH grant DK43135. F.H.B. was supported by NIH grant HL58688 and is a paid consultant of Novartis Pharmaceutical. R.A.F. and R.J.D. are investigators of the Howard Hughes Medical Institute.

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Correspondence to Augustine M.K. Choi.

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Otterbein, L., Bach, F., Alam, J. et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6, 422–428 (2000). https://doi.org/10.1038/74680

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