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.

The immune system protects from infections primarily by detecting and eliminating the invading pathogens; however, the host organism can also protect itself from infectious diseases by reducing the negative impact of infections on host fitness. This ability to tolerate a pathogen’s presence is a distinct host defense strategy, which has been largely overlooked in animal and human studies. Introduction of the notion of “disease tolerance” into the conceptual toolkit of immunology will expand our understanding of infectious diseases and host pathogen interactions. Analysis of disease tolerance mechanisms should provide new approaches for the treatment of infections and other diseases.

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe(2+), carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism underlying this cytoprotective effect relies on the ability of HO-1 to catabolize free heme and prevent it from sensitizing cells to undergo programmed cell death. This cytoprotective effect inhibits the pathogenesis of a variety of immune-mediated inflammatory diseases.

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