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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References
Tenhunen, R., Marver, H.S. & Schmid, R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc. Natl. Acad. Sci. USA 61 748–755 (1968).
Nath, D.A., Balla, G., Vercelotti, G.M. & Jacob, J. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J. Clin. Invest. 90 267–270 (1992).
Poss, K.D. & Tonegawa, S. Reduced stress defense in heme oxygenase deficient cells. Proc. Natl. Acad. Sci. USA 94 10925–10930 (1997).
Yachie, A., Niida, Y., Wada, T., Igarashi, N. & Kaneda, H. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103 129–135 (1999).
Otterbein, L.E., Sylvester, S. L. & Choi, A.M.K. Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. Am. J. Respir. Cell. Mol. Biol. 13 595–601 (1995).
Lee, P.J., Alam, J., Wiegand, G.W. & Choi, A.M.K. Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proc. Natl. Acad. Sci. USA. 93 10393–10398 (1996).
Otterbein, L.E. et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J. Clin. Invest. 103 1047–1054 (1999).
Parillo, J.E., Parker, M.M., Natanson, A.F., Suffredini, R.L. & Danner, R.E. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy. Ann. Intern. Med. 113 991–992 (1992).
Beutler, B, Krochin, N., Milsark, I.W., Luedke, C. & Cerami, A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 232, 977–980 (1986).
Netea, M. G., Kullberg, B. J. & van der Meer, J. W. Lipopolysaccharide-induced production of tumor necrosis factor and interleukin-1 is differentially regulated at the receptor level: the role of CD14-dependent and CD14-independent pathways. Immunology 94 340–344 (1998).
Howard, M., Muchamuel, T., Andrade, S. & Menon, S. Interleukin-10 protects mice from lethal endotoxemia. J. Exp. Med. 177 1205–1208 (1993).
Yang, R. et al. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signaling. Nature 395 284–288 (1998).
Chow, J.C., Young, D.W., Golenbock, D.T., Christ, W.J. & Gusovsky, F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 274 10689–10692 (1999).
Hambleton, J., Weinstein, S.L., Lem, L. & DeFranco, A.L. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc. Natl. Acad. Sci. USA 93 2274–2778 (1996).
Han, J., Lee, J.D., Bibbs, L. & Ulevitch, R.J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265 808–811 (1994).
Raingeaud, J., Gupta, S., Han, J., Ulevitch, R.J. & Davis, R.J. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270 7420–7426 (1995).
Thomassen, M.J. et al. Nitric oxide inhibits inflammatory cytokine production by human alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 17 279–283 (1997).
Morita, T., Perrella, M.A., Lee, M. & Kourembanas, S. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. Proc. Natl. Acad. Sci. USA 92 1475–1479 (1995).
Verma, A., Hirsch, D.J., Glatt, C.E., Ronnett, G.V. & Snyder, S.H. Carbon monoxide, a putative neural messenger. Science 259 381–384 (1993).
Tetreau, C., Tourbez, M., Gorren, A., Mayer, B. & Lavalette, D. Dynamics of carbon monoxide binding with neuronal nitric oxide synthase. Biochem. 38 7210–7218 (1999).
Derijard, B. et al. Independent human MAP kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267 682–685 (1995).
Raingeaud, J., Whitmarsh, A.J., Barrett, T., Derijard, B. & Davis, R.J. MKK3 and MKK6 regulation of gene expression is mediated by the p38 MAP kinase signal transduction pathway. Mol. Cell. Biol. 16 1247–1255 (1996).
Bauss, F., Droge, W. & Manel, D.N. Tumor necrosis factor mediates endotoxic shock in mice. Infect. Immun. 55 1622–1625 (1987).
Badger, A.M. et al. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J. Pharm. Exp. Ther. 279 1453–1461 (1996).
Wysk, M., Yang, D., Lu, H-T., Flavell, R.A. & Davis, R.J. TNF-induced cytokine expression mediated by the p38 MAP kinase activator MKK3. Proc. Natl. Acad. Sci. USA 96 3763–3768 (1999).
Geppert, T.D., Whitehurst, C.E., Thompson, P. & Beutler, B. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol. Med. 1 93–103 (1994).
Stocker, R., Yamamoto, Y., McDonagh, A.F., Glazer, A.N. & Ames, B.N. Bilirubin is an antioxidant of possible physiological importance. Science 235 1043–1046 (1987).
Llesuy, S. & Tomaro, M. Heme oxygenase and oxidative stress. Evidence of involvement of bilirubin as physiological protector against oxidative damage. Biochim. Biophys. Acta 1223 9–14 (1994).
Balla, J. et al. Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc. Natl. Acad. Sci. USA 90 9285–9289 (1993).
Stupfel, M. & Bouley, G. Physiological and biochemical effects on rats and mice exposed to small concentrations of carbon monoxide for long periods. Ann. NY Acad. Sci. 174 342–368 (1970).
Foey, A. D. et al. Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of the p38 and p42/44 mitogen-activated protein kinases. J. Immunol. 160 920–928 (1998).
Elbirt, K.K., Whitmarsh, A.J. & Davis, R.J. Mechanism of sodium arsenite-mediated induction of heme oxygenase-a in hepatoma cells: involvement of MAP kinase. J. Biol. Chem. 273 8922–8931 (1998).
Szabo, C., Hasko, G., Nemeth, Z.H. & Vizi, E.S. Calcium entry blockers increase interleukin-10 production in endotoxemia. Shock 7 304–307 (1997).
Nemeth, Z.H., Hasko, G., Szabo, C. & Vizi, E.S. Amrinone and theophylline differentially regulate cytokine and nitric oxide production in endotoxemic mice. Shock 7 371–375 (1997).
Hasko, G., Szabo, C., Nemeth, Z.H., Salzman, A.L. & Vizi, E.S. Suppression of IL-12 production by phosphodiesterase inhibition in murine endotoxemia is interleukin-10 independent. Eur. J. Immunol. 28 468–472 (1998).
Jongeneel, C.V. Regulation of the TNF alpha gene. Prog. Clin. Biol. Res. 388 367–381 (1994).
Han, J., Brown, T. & Beutler, B. Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level. J. Exp. Med. 171 465–475 (1990).
Han, J.H., Beutler, B. & Huez, G. Complex regulation of tumor necrosis factor mRNA turnover in lipopolysaccharide-activated macrophages. Biochim. Biophys. Acta 1090 22–28 (1991).
Soares, M.P. et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nature Med. 4 1073–1077 (1998).
Otterbein, L.E., Mantell, L.L. & Choi, A.M.K. Carbon monoxide provides protection against hyperoxic lung injury. Am. J. Physiol. 276 L688–L694 (1999).
Lu, H-T. et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18 1845–1857 (1999).
Shibahara, S., Meller, R., Taguchi, H. & Yoshida, T. Cloning and expression of cDNA for ratheme oxygenase. Proc. Natl. Acad. Sci. USA 82 7865–7869 (1985).
Fuhlbrigge, R.C., Fine, S.M., Unanue, E.R. & Chaplin, D.D. Expression of membrane interleukin 1 by fibroblasts transfected with murine pro-interleukin 1 alpha cDNA. Proc. Natl. Acad. Sci. USA 85 5649–5653 (1988).
Alam, J. Multiple elements within the 5′ distal enhancer of the mouse heme oxygenase-1 gene mediate induction by heavy metals. J. Biol. Chem. 269 25049–25056 (1994).
Gunther, S., Alexander, R.W., Atkinson, W.J. & Gimbrone, M.A. Functional angiotensin II receptors in cultured vascular smooth muscle cells. J. Cell. Biol. 92 289–298 (1982).
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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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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DOI: https://doi.org/10.1038/74680
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