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Heme Oxygenase-1 : Its Therapeutic Roles in Inflammatory Diseases

  • Pae, Hyun-Ock (Department of Microbiology and Immunology, Wonkwang University School of Medicine) ;
  • Chung, Hun-Taeg (Department of Microbiology and Immunology, Wonkwang University School of Medicine)
  • Published : 2009.02.28
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Abstract

Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.

Keywords

References

  1. Kumar S, Bandyopadhyay U: Free heme toxicity and its detoxification systems in human. Toxicol Lett 157;175-188, 2005 https://doi.org/10.1016/j.toxlet.2005.03.004
  2. Ryter SW, Tyrrell RM: The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 28;289-309, 2000 https://doi.org/10.1016/S0891-5849(99)00223-3
  3. Maines MD: Heme oxygenase: Funcion, multiplicity, regulatory mechanisms, and clinical applications. FASEB J 2;2557-2568, 1988
  4. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, Figdor CG: Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev 55;551-571, 2003 https://doi.org/10.1124/pr.55.3.5
  5. Immenschuh S, Ramadori G: Gene regulation of heme oxygenase-1 as a therapeutic target. Biochem Pharmacol 60;1121-1128,2000 https://doi.org/10.1016/S0006-2952(00)00443-3
  6. Abraham NG, Kappas A: Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60;79-127, 2008
  7. Willoughby Da, Moore AR, Colville-Nash PR, Gilroy D: Resolution of inflammation. Int J Immunopharmacol 22;1131-1135, 2000 https://doi.org/10.1016/S0192-0561(00)00064-3
  8. Owuor ED, Kong AN : Antioxidants and oxidants regulated signal transduction pathways. Biochem Phamacol 64;765-770, 2002 https://doi.org/10.1016/S0006-2952(02)01137-1
  9. Farombi EO, Surh YJ: Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol 39;479-497, 2006 https://doi.org/10.5483/BMBRep.2006.39.5.479
  10. Ryter SW, Otterbein LE, Morse D, Choi AM: Heme oxyhenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem 234;249-263, 2002 https://doi.org/10.1023/A:1015957026924
  11. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN:Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66;11580-11584, 2006 https://doi.org/10.1158/0008-5472.CAN-06-3562
  12. Kim EH, Na HK, Surh YJ: Upregulation of VEGF by 15-deoxy-Delta 12,14-jprostaglandin J2 via heme oxygen-ase-1 and ERK1/2 signaling in MCF-7 cells. Ann N Y Acad Sci 1090;375-384, 2006 https://doi.org/10.1196/annals.1378.041
  13. Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, Mussler N: Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygen-ase-1 via the MAPK/Nrf2 pathways. J Hepatol 47;253-261, 2007 https://doi.org/10.1016/j.jhep.2007.02.008
  14. Takahashi T, Shimizu H, Morimatsu H, Lnoue K, Akagi R, Morita K, Sassa S: Heme oxygenase-1: a fundamental guardian against oxidative tissue injuries in acute inflammation. Mini Rev Med Chem 7;745-753, 2007 https://doi.org/10.2174/138955707781024517
  15. Ryter SW, Alam J, Choi AM: Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86;583-650, 2006 https://doi.org/10.1152/physrev.00011.2005
  16. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Cohi AM: 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
  17. Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, Chung KR, Chung HT: Carbon monoxide produced by heme oxygenase - 1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 172;4744-4751, 2004
  18. Suh GY, Jin Y, Yi AK, Wang XM, Choi AM: CCAAT/enhancer-binding protein mediates carbon monoxide-induced suppression of cyclooxygenase-2. Am J Respir Cell Mol Biol 35;220-226, 2006 https://doi.org/10.1165/rcmb.2005-0154OC
  19. Megias J, Busserolles J, Alcaraz MJ: The carbon monoxide-releasing molecule CORM-2 inhibits the inflammatory response induced by cytokines in Caco-2 cells. Br J Pharmacol 150;977-986, 2007 https://doi.org/10.1038/sj.bjp.0707184
  20. Ollinger R, Wang H, Yamashita K, Wegiel B, Thomas M, Margreiter R, Bach FH: Therapeutic applications of bilirubin and biliverdin in transplantation. Antioxid Redox Signal 9;2175-2185, 2007 https://doi.org/10.1089/ars.2007.1807
  21. Yamashita K, McDaid J, Ollinger R, Tsui TY, Berberat PO, Usheva A, Csizmadia E, Smith RN, Soares MP, Bach FH: Biliberdin, a natural product of heme catabolism, induces tolerance to cardiac allografts. FASEB J 18;765-767, 2004
  22. Sarady-Andrews JK, Liu F, Gallo D, Nakao A, Oberhaus M, Ollinger R, Choi AM, Otterbein LE: Biliverdin administration protects against endotoxin-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol 289;L1131-L1137, 2005 https://doi.org/10.1152/ajplung.00458.2004
  23. Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui TY, Bach FH: Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation, J Immunol 172;3553-3563, 2004 https://doi.org/10.4049/jimmunol.172.6.3553
  24. Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Eaton JW, Balla G: Heme, heme oxygenase and ferritin in vascular endothelial cell injury. Mol Nutr Food Res 49;1030-1043, 2005 https://doi.org/10.1002/mnfr.200500076
  25. Aust SD: Ferritin as a source of iron and protection from iron-induced toxicities. Toxicol Lett 82-83;941-944, 1995 https://doi.org/10.1016/0378-4274(95)03605-9
  26. Schaer CA, Schoedon G, Imhof A, Kurrer MO, Schaer DJ: Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Circ Res 99;943-950, 2006 https://doi.org/10.1161/01.RES.0000247067.34173.1b
  27. Kapturczak MH, Wasserfall C, Brusko T, Campbell-Thompson M, Ellis TM, Atkinson MA, Agarwal A: Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am J Pathol 165;1045-1053, 2004 https://doi.org/10.1016/S0002-9440(10)63365-2
  28. Tracz MJ, Juncos JP, Croatt AJ, Ackerman AW, Crande JP, Knutson KL, Kane GC, Terzic A, Griffin MD, Nath KA: Deficiency of heme oxygenase-1 impairs renal hemody-namics and exaggerates systemic inflammatory responses to renal ischemia. Kidney Int 72;1073-1080, 2007 https://doi.org/10.1038/sj.ki.5002471
  29. Koizumi S: Human heme oxygenase-1 deficiency: a lesson on serendipity in the discovery of the novel disease. Pediatr Int 49;125-132, 2007
  30. Kawashima A, Oda Y, Yachie A, Koizumi S, Nakanishi I: Heme oxygenase-1 deficiency: the first autopay case. Hum Pathol 33;125-130, 2002 https://doi.org/10.1053/hupa.2002.30217
  31. Baecher-Allen C, Hafler DA: Human regulatory T cells and their role in autoimmune disease. Immunol Rev 212;203-216, 2006 https://doi.org/10.1111/j.0105-2896.2006.00417.x
  32. Zelenay S, Chora A, Soares MP, Demengeot J: Heme oxygenase-1 is not required for mouse regulatory T cell development and function, Int Immunol 19;11-18, 2007
  33. George JF, Braun A, Brusko TM, Joseph R, Bolisetty S, Wasserfall CH, Atkinson MA, Agarwal A, Kapturczak MH: Suppression by $CD4^{+}CD25^{+}$ regulatory T cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol 173;154-160, 2008 https://doi.org/10.2353/ajpath.2008.070963
  34. Maeda S, Makatsuka I, Hayashi Y, Higuchi H, Shimada M, Miyawaki T: Heme oxygenase-1 induction in the brain during lipopolysaccharide-induced acute inflammation. Neuropsychiatr Dis Treat 4;663-6678, 2008
  35. Tamion F, Richard V, Renet S, Thuillez C: Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model. Am J Physiol Gastrointest Liver Physiol 293;G1308-G1314, 2007 https://doi.org/10.1152/ajpgi.00154.2007
  36. Tracz MJ, Juncos JP, Grande JP, Croatt AJ, Ackeman AW, Rajagopalan G, Knutson KL, Badley AD, Griffin MD, Alam J, Nath KA: Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1 mice. Am J Pathol 170;1820-1830, 2007 https://doi.org/10.2353/ajpath.2007.061093
  37. Tamion F, Richard V, Renet S, Thuillez C: Protective effects of heme-oxygenase expression against endotoxic shock: inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10. J Trauma 61;1078-1084, 2006 https://doi.org/10.1097/01.ta.0000239359.41464.ef
  38. Moreto V, Stabile AM, Antunes-Rodrigues J, Camio EC: Role of heme-oxygenase pathway on vasopressin deficiency during endotoxemic shock-like conditions. Shock 26;472-476, 2006 https://doi.org/10.1097/01.shk.0000230301.86139.6a
  39. Chang KY, Tsai PS, Huang TY, Wang TY, Yang S, Huang CJ: HO-1 mediates the effects of HBO pretreatment against sepsis. J Surg Res 136;143-153, 2006 https://doi.org/10.1016/j.jss.2006.06.004
  40. Poole B, Wang W, Chen YC, Zolty E, Falk S, Mitra A, Schrier R: Role of heme oxygenase-1 in endotoxemic acute renal failure. Am J Physiol Renal Physiol 289;F1382-F1385, 2005 https://doi.org/10.1152/ajprenal.00402.2004
  41. Wiesel P, Patel AP, DiFonzo N, Marria PB, Sim CU, Pellacani A, Maemura K, LeBlanc BW, Marino K, Doerschuk CM, Yet SK, Lee ME, Perrella MA: Endotoxin-induced mortality is relatied to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygen ase-1 deficien mice. Circulation 102;3015-3022, 2000 https://doi.org/10.1161/01.CIR.102.24.3015
  42. Suzuki T, Takahashi T, Yamasaki A, Jujiwara T, Hirakawa M, Akagi R: Tissue-specific gene expression of heme oxygenase-1 (HO-1) and non-specific delta-aminolevulinate synthase (ALAS-N) in a rat model of septic multiple organ dysfunction syndrome. Biochem Pharmacol 60;275-283, 2000 https://doi.org/10.1016/S0006-2952(00)00324-5
  43. Mohri T, Ogura H, Koh T, Fujita K, Sumi Y, Yoshiya K, Matsushima A, Hosotsubo H, Kuwagata Y, Tanaka H, Shimazu T, Sugimoto H: Enhanced expression of intracellular heme oxygenase-1 in deactivated monocytes from patients with severe systemic inflammatory response syndrome. J Trauma 61;616-623, 2006 https://doi.org/10.1097/01.ta.0000238228.67894.d7
  44. Chung SW, Liu X, Macias AA, Baron RM, Perrella MA: Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J Clin Invest 118;239-247, 2008
  45. Becker T, Zu Vilsendorf AM, Tervish T, Klempnauer J, J?ms A: Induction of heme oxygenase-1 improves the survival of pancreas grafts by prevention of pancreatitis after transplantation. Transplantation 84;1644-1655, 2007 https://doi.org/10.1097/01.tp.0000290233.81395.81
  46. Du D, Chang S, Chen B, Zhou H, Chen ZK: Adenovirusmediated heme oxygenase transfer inhibits graft arteriosclerosis in rat aortic transplants. Transplant Proc 39;3446-3448, 2007 https://doi.org/10.1016/j.transproceed.2007.03.114
  47. Laumonier R, Yang S, Konig S, Chauveau C, Anegon I, Hoffmeyer P, Menetrey J: Lentivirus mediated HO-1 gene transfer enhances myogenic precursor cell survival afer autologyus transplantation in pig. Mol Ther 6;404-410, 2008
  48. Zhen-Wei X, Jian-Le S, Qi Q, Wen-Wei Z, Xue-Hong Z, Zi-Li Z: Heme oxygenase-1 improves the survivial of discordant cardiac xenograft through its anti-inflammatory and anti-apoptotic effects. Pediatr Transplant 11;850-859, 2007
  49. Lee SS, Gao W, Mazzola S, Thomas MN, Csizmadia E, Otterbein LE, Bach FH, Wang H: Heme oxygenase-1, carbon monoxide, and bilirubin inuce tolerance in recipients toword islet allografts by modulating T regulatory cells. FASEB J 21;3450-3457, 2007 https://doi.org/10.1096/fj.07-8472com
  50. Schnickel GT, Hsieh GR, Kachikwu EL, Garcia C, Shefizadeh A, Fishbein MC, Ardehali A: Cytoprotective gene HO-1 and chronic rejection in heart transplantation. Transplant Proc 38;3259-3262, 2006 https://doi.org/10.1016/j.transproceed.2006.10.156
  51. Yamashita K, Ollinger R, McDaid J, Sakahama H, Wang H, Tyagi S, Csizmadia E, Smith NR, Soares MP, Bach FH: Heme oxygenase-1 is essential for and promotes tolerance to transplanted organs. FASEB J 20;776-778, 2006
  52. Tu CF, Kuo CH, Juang JH: Effects of heme oxygenase-1 transgenic islets on transplantation. Transplant Proc 37;3463-3467, 2005 https://doi.org/10.1016/j.transproceed.2005.09.022
  53. Wang H, Lee SS, Gao W, Czismadia E, McDid J, Ollinger R, Soares MP, Yamashita K, Bach FH: Donor trantment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes 54;1400-1406, 2005 https://doi.org/10.2337/diabetes.54.5.1400
  54. Kobayashi T, Sato Y, Yamamoto S, Takeishi T, Hirano K, Watanabe T, Takano K, Naito M, Hatakeyama K: Augmentation of heme oxygenase-1 expression in the graft immediately after implantation in adult living-donor liver transplantation. Transpantation 79;977-980, 2005 https://doi.org/10.1097/01.TP.0000155245.85967.AD
  55. Martins PN, Kessler H, Jurisch A, Reutzel-Selke A, Kramer J, Pascher A, Pratschke J, Neuhaus P, Volk HD, Tullius SG: Induction of heme oxygenase-1 in the donor reduces graft immunogenicity. Transplant Proc 37;924-386, 2005
  56. Martins PN, Reuzel-Selke A, Jurisch A, Atrott K, Pascher A, Pratschke J, Buelow R, Meuhaus P, Volk HD, Tullius SG: Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration. Transplant Proc 37;379-381, 2005 https://doi.org/10.1016/j.transproceed.2004.11.079
  57. Bedard EL, Jiang J, Parry N, Wang H, Liu W, Garcia B, Kim P, Chakrabarti S, Buelow R, Zhong R: Pertiransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection. Transpl Int 18;341-349, 2005 https://doi.org/10.1111/j.1432-2277.2004.00062.x
  58. Sato K, Balla J, Otterbein L, Smith RN, Brouard S, Lin Y, Csizmadia E, Sevigny J, Robson SC, Vercellotti G, Choi AM, Bach FH, Soares MP: Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardic transplants. J Immunol 166;4185-4194, 2001 https://doi.org/10.4049/jimmunol.166.6.4185
  59. Nakao A, Choi AM, Murase N: Protective effect of arbon monoxide in transplantation. J Cell Mol Med 10;650-671, 2006 https://doi.org/10.1111/j.1582-4934.2006.tb00426.x
  60. Wagner M, Cadetg P, Ruf R, Mazzucchelli L, Ferrari P, Redaelli CA: Heme oxygenase-1 attenuates ischemia/reperfusion-induced apoptosis and improves survival in rat renalallografts. Kidney Int 63;1564-1573, 2003 https://doi.org/10.1046/j.1523-1755.2003.00897.x
  61. Bach FH: Heme oxygenase-1 and transplantation tolerance. Hum Immunol 67;430-432, 2006 https://doi.org/10.1016/j.humimm.2006.03.006
  62. Shen WL, Zhong MF, Ding WL, Wang J, Zheng L, Zhu P, Wang BS, Higashino H, Chen H: Elevated catalase and heme oxygenase-1 may contribute to improved postischasmic cardiac function in long-term type 1 diabetes. Clin Exp Phamacol Physiol 35;820-826, 2008 https://doi.org/10.1111/j.1440-1681.2008.04937.x
  63. Jang JU, Lee SH, Choi CU, Bahk SC, Chung HT, Yang YS: Effects of heme oxygenase-1 inducer and inhibitor on experimental autoimmune uveoretinitis. Korean J Ophthalmol 21;238-243, 2007 https://doi.org/10.3341/kjo.2007.21.4.238
  64. Hu CM, Lin HH, Chiang MT, Chang PF, Chau LY: Systemic expression of heme oxygenase-1 ameliorates type 1 diabetes in NOD mice. Diabetes 56;1240-1247, 2007 https://doi.org/10.2337/db06-0495
  65. Li M, Peterson S, Husney D, Inaba M, Guo K, Kappas A, Itehara S, Abraham NG: Long-lasting expression of HO-1 delays progression of type 1 diabetes in NOD mice. Cell Cycle 6;567-571, 2007 https://doi.org/10.4161/cc.6.5.3917
  66. Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, Ho PP, Lee LY, Sobel RA, Steinman L, Soares MP: Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammaion. J Clin Invest 117;438-447, 2007 https://doi.org/10.1172/JCI28844
  67. Kobayashi H, Takeno M, Saito T, Takeda Y, Kirino Y, Noyori K, Hayashi T, Ueda A, Ishigatsubo Y: Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis. Arthrtis Rheum 54;1132-1142, 2006 https://doi.org/10.1002/art.21754
  68. Chakrabarty A, Emerson MR, LeVine SM: Heme oxygenase-1 in SJL. mice with experimental allergic encephalomyelitis autoimmune encephalomyelitis. Meuroreport 12;1841-1845, 2001
  69. Liu Y, Zhu B, Luo L, Li P, Paty DW, Cynader MS: Heme oxygenase-1 plays and important protective role in experimental autoimmune encephlomyelitis, Neuroreport 12;1841-1845, 2001 https://doi.org/10.1097/00001756-200107030-00016
  70. Li M, Peterson S, Husney D, Inaba M, Guo K, Terada E, Morita T, Patil K, Kappas A, Ikehara S, Abraham NG: Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin. Antoxid Reox Signal 9;855-863, 2007 https://doi.org/10.1089/ars.2007.1568
  71. Pae HO, Lee YC, Chung HT: Heme oxygenase-1 and carbon monoide: emerging therapeutic targets in inflammation and allergy. Recent Pat Inflamm Allergy Drug Discov 2;159-165, 2008 https://doi.org/10.2174/187221308786241929
  72. Almolki A, Taille C, Martin GF, Jose PJ, Zedda C, Conti M, Megret J, Henin D, Aubier M, Boczkowski J: Heme oxygenase attenuates allergen-induced airway inflammation and hyperreacitity in guinea pigs. Am J Physiol Lung Cell Mol Physiol 287;L23-L34, 2004
  73. Kirino M, Kirino Y, Takeno M, Nagashima Y, Takahashi K, Kobayashi M, Murakami S, Hirasawa T, Ueda A, Aihara M, Ikezawa Z, Ishigatsubo Y: Heme oxygenase 1 attenuates the development of atopic dematitis-like lesions in mice: impliations for human disease. J Allergy Clin Immunol 122;290-297, 2008 https://doi.org/10.1016/j.jaci.2008.05.031
  74. Takamiya R, Murakami M, Kajimura M, Goda N, Makino N, Takamiya Y, yamaguchi T, Ishimura Y, Hozumi N, Suematsu M: Stabilization of mast cells by heme oxygenase-1: an anti-inflammatory role. Am J Physiol Heart Circ Physiol 283;H861-H870, 2002 https://doi.org/10.1152/ajpheart.00740.2001
  75. Vannaci A, Baronti R, Zagli G, Marzocca C, Pierpaoli S, Bani D, Passani MB, Mannaioni PF, Masini E: Carbon monoxide modulates the response of human basophils to FoepsilonRI simulation through the heme oxygenase pahtway. Eur J Phamaol 465;289-297, 2003 https://doi.org/10.1016/S0014-2999(03)01489-4
  76. Xia ZW, Xu LQ, Zhong WW, Wei JJ, Li NL, Shao J, Li YZ, Yu SC, Zhang ZL: Heme oxygenase-1 atenuates ovalbumin-induced airway inflammation by up-regulation of foxp3 T-regulatory cells, interleukin-10, and membranebound transforming growth facor-1. Am J Pathol 171;1904-1914, 2007 https://doi.org/10.2353/ajpath.2007.070096
  77. Rushworth SA, O'Connell MA: Hame oxygenase-1 in inflammation. Biochem Soc Trans 32;1093-1094, 2004 https://doi.org/10.1042/BST0321093