Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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The Role of Nrf2 in Cellular Innate Immune Response to Inflammatory Injury

  • Kim, Ji-Young (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Surh, Young-Joon (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
  • Published : 2009.12.01
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Abstract

Nuclear factor erythroid derived 2-related factor-2 (Nrf2) is a master transcription regulator of antioxidant and cytoprotective proteins that mediate cellular defense against oxidative and inflammatory stresses. Disruption of cellular stress response by Nrf2 deficiency causes enhanced susceptibility to infection and related inflammatory diseases as a consequence of exacerbated immune-mediated hypersensitivity and autoimmunity. The cellular defense capacity potentiated by Nrf2 activation appears to balance the population of $CD4^+$ and $CD8^+$ of lymph node cells for proper innate immune responses. Nrf2 can negatively regulate the activation of pro-inflammatory signaling molecules such as p38 MAPK, NF-${\kappa}B$, and AP-1. Nrf2 subsequently functions to inhibit the production of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, COX-2 and iNOS. Although not clearly elucidated, the antioxidative function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the expression of pro-inflammatory mediators.

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References

  1. Aburaya, M., Tanaka, K, Hoshino, T, Tsutsumi, S., Suzuki, K, Makise, M., Akagi, R. and Mizushima, T. (2006). Heme oxygenase-1 protects gastric mucosal cells against non-steroidal anti-inflammatory drugs. J BioI. Chem., 281, 33422-33432 https://doi.org/10.1074/jbc.M602074200
  2. Almolki, A, Guenegou, A, Golda, S., Boyer, L., Benallaoua, M., Amara, N., Bachoual, R., Martin, C., Rannou, F., Lanone, S., Dulak, J., Burgel, P.R., El-Benna, J., Leynaert, AB., Aubier, M. and Boczkowski, J. (2008). Heme oxygenase-1 prevents airway mucus hypersecretion induced by cigarette smoke in rodents and humans. Am. J. Pathol., 173, 981-992 https://doi.org/10.2353/ajpath.2008.070863
  3. Angelov, N., Moutsopoulos, N., Jeong, M.J., Nares, S., Ashcroft, G and Wahl, S.M. (2004). Aberrant mucosal wound repair in the absence of secretory leukocyte protease inhibitor. Thrornb. Haernost., 92, 288-297
  4. Arisawa, T, Tahara, T, Shibata, T, Nagasaka, M., Nakamura, M., Kamiya, Y, Fujita, H., Hasegawa, S., Takagi, T, Wang, FY, Hirata, I. and Nakano, H. (2007). The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis. Intl. J. Mol. Med., 19, 143-148
  5. Asada, K., Sasaki, S., Suda, I., Chida, K. and Nakamura, H. (2004). Antiinflammatory roles of peroxisome proliferatoractivated receptor gamma in human alveolar macrophages. Am. J. Respir. Crit. Care Med., 169, 195-200 https://doi.org/10.1164/rccm.200207-740OC
  6. Asghar, M., George, L. and Lokhandwala, M.F (2007). Exercise decreases oxidative stress and inflammation and restores renal dopamine 01 receptor function in old rats. Am. J. Physiol. Renal Physiol., 293, F914-919 https://doi.org/10.1152/ajprenal.00272.2007
  7. Berberat, PO., YI, AR., Yamashita, K., Warny, M.M., Csizmadia, E., Robson, S.C. and Bach, FH. (2005). Heme oxygenase-1-generated biliverdin ameliorates experimental murine colitis. Inflammatory Bowel Diseases, 11, 350-359 https://doi.org/10.1097/01.MIB.0000164017.06538.8a
  8. Bingle, L. and Tetley, TO. (1996). Secretory leukoprotease inhibitor: partnering alpha 1-proteinase inhibitor to combat pulmonary inflammation. Thorax, 51, 1273-1274 https://doi.org/10.1136/thx.51.12.1273
  9. Brandsma, C.A., Hylkema, M.N., van der Strate, S.W, Siebos, O.J., Luinge, M.A., Geerlings, M., Timens, W, Postma, O.S. and Kerstjens, H.A. (2008). Heme oxygenase-1 prevents smoke induced B-cell infiltrates: a role for regulatory T cells? Respir. Res., 9, 17 https://doi.org/10.1186/1465-9921-9-17
  10. Braun, S., Hanselmann, C., Gassmann, M.G, auf dem Keller, U., Born-Berclaz, C., Chan, K., Kan, YW and Werner, S. (2002). Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol. Cell. BioI., 22, 5492-5505 https://doi.org/10.1128/MCB.22.15.5492-5505.2002
  11. Calabrese, V., Ravagna, A, Colombrita, C., Scapagnini, G, Guagliano, E., Calvani, M., Butterfield, O.A. and Giuffrida, Stella, AM. (2005). Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2. J. Neurosci. Res., 79, 509-521 https://doi.org/10.1002/jnr.20386
  12. Chaea, H.J., Kim, H.R., Kang, YJ., Hyun, K.C., Kim, H.J., Seo, H.G, Lee, J.H., Yun-Choi, H.S. and Chang, K.C. (2007). Heme oxygenase-1 induction by (S)-enantiomer of YS-51 (YS-51 S), a synthetic isoquinoline alkaloid, inhibits nitric oxide production and nuclear factor-kappaB translocation in ROS 17/2.8 cells activated with inflammatory stimulants. Int. Immunopharmacol., 7, 1559-1568 https://doi.org/10.1016/j.intimp.2007.07.023
  13. Chan, J.Y. and Kwong, M. (2000). Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochim. Biophys. Acta, 1517,19-26 https://doi.org/10.1016/S0167-4781(00)00238-4
  14. Chen, X.L. and Kunsch, C. (2004). Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Current Pharmaceutical Design, 10, 879-891 https://doi.org/10.2174/1381612043452901
  15. Chen, X.L., Dodd, G, Thomas, S., Zhang, X., Wasserman, M.A., Rovin, B.H. and Kunsch, C. (2006). Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am. J. Physiol., 290, H1862-1870
  16. Chen, X.L., Varner, S.E., Rao, AS., Grey, J.Y., Thomas, S., Cook, C.K., Wasserman, M.A., Medford, R.M., Jaiswal, AK. and Kunsch, C. (2003). Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. J. BioI. Chem., 278, 703-711 https://doi.org/10.1074/jbc.M203161200
  17. Cho, H.Y., Reddy, S.P and Kleeberger, S.R. (2006). Nrf2 defends the lung from oxidative stress. Antioxidants & Redox Signaling, 8, 76-87 https://doi.org/10.1089/ars.2006.8.76
  18. Cho, H.Y., Jedlicka, AE., Reddy, S.P, Zhang, L.Y, Kensler, TW and Kleeberger, S.R. (2002a). Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am. J. Res. Cell Mol. Bioi., 26, 42-51 https://doi.org/10.1165/ajrcmb.26.1.4536
  19. Cho, H.Y., Jedlicka, AE., Reddy, S.P, Kensler, TW, Yamamoto, M., Zhang, L.Y and Kleeberger, S.R. (2002b). Role of NRF2 in protection against hyperoxic lung injury in mice. Am. J. Res. Cell Mol. Bioi., 26, 175-182 https://doi.org/10.1165/ajrcmb.26.2.4501
  20. Chu, FF, Esworthy, R.S. and Ooroshow, J.H. (2004). Role of Se-dependent glutathione peroxidases in gastrointestinal inflammation and cancer. Free Radic. BioI. Med., 36, 1481-1495 https://doi.org/10.1016/j.freeradbiomed.2004.04.010
  21. Chung, S.W, Liu, X., Macias, AA, Baron, R.M. and Perrella, M.A. (2008). Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J. Clin. Investig., 118, 239-247 https://doi.org/10.1172/JCI32730
  22. Cohen, J. (2002). The immunopathogenesis of sepsis. Nature, 420, 885-891 https://doi.org/10.1038/nature01326
  23. Criddle, O.N., Gerasimenko, JV, Baumgartner, HK, Jaffar, M., Voronina, S., Sutton, R., Petersen, O.H. and Gerasimenko, OV (2007). Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death Differ., 14, 1285-1294 https://doi.org/10.1038/sj.cdd.4402150
  24. Cuadrado, A and Rojo, AI. (2008). Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Current Pharmaceutical Design, 14, 429-442 https://doi.org/10.2174/138161208783597407
  25. Cuzzocrea, S., Costantino, G, Zingarelli, B., Mazzon, E., Micali, A and Caputi, AP (1999). The protective role of endogenous glutathione in carrageenan-induced pleurisy in the rat. Eur. J. Pharmacol., 372, 187-197 https://doi.org/10.1016/S0014-2999(99)00200-9
  26. d'Alessio, P., Moutet, M., Coudrier, E., Oarquenne, S. and Chaudiere, J. (1998). ICAM-1 and VCAM-1 expression induced by TNF-alpha are inhibited by a glutathione peroxidase mimic. Free Radic. Bioi. Med., 24, 979-987 https://doi.org/10.1016/S0891-5849(97)00396-1
  27. Oas, A, Kole, L., Wang, L., Barrios, R., Moorthy, B. and Jaiswal, AK. (2006). BALT development and augmentation of hyperoxic lung injury in mice deficient in NQ01 and NQ02. Free Radic. Bio.I Med., 40, 1843-1856 https://doi.org/10.1016/j.freeradbiomed.2006.01.025
  28. Oinkova-Kostova, AT, Holtzclaw, WO., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y, Yamamoto, M. and Talalay, P (2002). Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. USA, 99,11908-11913 https://doi.org/10.1073/pnas.172398899
  29. Oinkova-Kostova, AT, Holtzclaw, WO. and Kensler, TW (2005a). The role of Keap1 in cellular protective responses. Chem. Res. Toxicol., 18, 1779-1791 https://doi.org/10.1021/tx050217c
  30. Oinkova-Kostova, A.T., Liby, K.T., Stephenson, K.K., Holtzclaw, WO., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, I., Gribble, GW, Sporn, M.B. and Talalay, P (2005b). Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Prac. Nat. Acad. Sci. USA, 102, 4584-4589 https://doi.org/10.1073/pnas.0500815102
  31. Ferrandiz, M.L., Maicas, N., Garcia-Arnandis, I., Terencio, M.C., Motterlini, R, Devesa, I., Joosten, LA, van den Berg, WB. and Alcaraz, M.J. (2008). Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis. Ann. Rheum. Dis., 67, 1211-1217 https://doi.org/10.1136/ard.2007.082412
  32. Flentjar, N.J., Crack, P.J., Boyd, R, Malin, M., de Haan, J.B., Hertzog, P, Kola, I. and Iannello, R (2002). Mice lacking glutathione peroxidase-1 activity show increased TUNEL staining and an accelerated inflammatory response in brain following a cold-induced injury. Exp. Neural., 177, 9-20 https://doi.org/10.1006/exnr.2002.7927
  33. Freitas, A, Alves-Filho, J.C., Secco, D.o., Neto, AF, Ferreira, S.H., Barja-Fidalgo, C. and Cunha, F.Q. (2006). Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation. Br. J Pharmacol., 149, 345-354 https://doi.org/10.1038/sj.bjp.0706882
  34. Gopalakrishnan, A and Kong, ANT (2008). Anticarcinogenesis by dietary phytochemicals: cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-kappa Band AP-1 in abnormal cancer cells. Food Chem. Toxicol., 46, 1257-1270 https://doi.org/10.1016/j.fct.2007.09.082
  35. Greaves, DR., Gough, P.J. and Gordon, S. (1998). Recent progress in defining the role of scavenger receptors in lipid transport, atherosclerosis and host defence. Curr. Opin. Lipidol., 9, 425-432 https://doi.org/10.1097/00041433-199810000-00006
  36. Halliwell, B. and Gutteridge, J.M.C. (2007). Free Radicals in Biology and Medicine. Oxford University Press, New York
  37. Hartl, D., Starosta, V, Maier, K., Beck-Speier, I., Rebhan, C., Becker, BF, Latzin, P., Fischer, R, Ratjen, F., Huber, RM., Rietschel, E., Krauss-Etschmann, S. and Griese, M. (2005). Inhaled glutathione decreases $PGE_2$ and increases lymphocytes in cystic fibrosis lungs. Free Radic. BioI. Med., 39,463-472 https://doi.org/10.1016/j.freeradbiomed.2005.03.032
  38. Hashimoto, S., Gon, Y, Matsumoto, K., Takeshita, I., MacHino, T and Horie, T (2001). Intracellular glutathione regulates tumour necrosis factor-alpha-induced p38 MAP kinase activation and RANTES production by human bronchial epithelial cells. Clin. Exp. Allergy, 31, 144-151
  39. Hassan, M.Q., Hadi, RA, AI-Rawi, l.S., Padron, VA and Stohs, S.J. (2001). The glutathione defense system in the pathogenesis of rheumatoid arthritis. J. Appl. Toxicol., 21, 69-73 https://doi.org/10.1002/jat.736
  40. Healy, l.R, Lee, N.H., Gao, X., Goldring, M.B., Talalay, P., Kensler, TW and Konstantopoulos, K. (2005). Divergent responses of chondrocytes and endothelial cells to shear stress: cross-talk among COX-2, the phase 2 response, and apoptosis. Prac. Natl. Acad. Sci. USA, 102, 14010-14015 https://doi.org/10.1073/pnas.0506620102
  41. Heiss, E., Herhaus, C., Klimo, K., Bartsch, H. and Gerhauser, C. (2001). Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J. BioI. Chem., 276, 32008-32015 https://doi.org/10.1074/jbc.M104794200
  42. Henriksen, PA, Hitt, M., Xing, l., Wang, J., Haslett, C., Riemersma, RA, Webb, D.J., Kotelevtsev, YV. and Sallenave, J.M. (2004). Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NFkappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. J. Immunol., 172, 4535-4544 https://doi.org/10.4049/jimmunol.172.7.4535
  43. Hong, F, Freeman, M.L. and Liebler, D.C. (2005). Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem. Res. Toxicol., 18, 1917-1926 https://doi.org/10.1021/tx0502138
  44. Horvath, K., Varga, C., Berko, A, Posa, A, Laszlo, F and Whittle, B.J. (2008). The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur. J Pharmacal., 581, 315-323 https://doi.org/10.1016/j.ejphar.2007.12.004
  45. Hubbs, AF, Benkovic, SA, Miller, D.B., O'Caliaghan, J.P., Battelli, L., Schwegler-Berry, D. and Ma, Q. (2007). Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am. J.Pathol., 170, 2068-2076 https://doi.org/10.2353/ajpath.2007.060898
  46. lizuka, T, Ishii, Y, Itoh, K., Kiwamoto, T, Kimura, T, Matsuno, Y, Morishima, Y, Hegab, AE., Homma, S., Nomura, A, Sakamoto, T, Shimura, M., Yoshida, A, Yamamoto, M. and Sekizawa, K. (2005). Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells, 10, 1113-1125 https://doi.org/10.1111/j.1365-2443.2005.00905.x
  47. Imaoka, H., Hoshino, T, Takei, S., Sakazaki, Y, Kinoshita, T, Okamoto, M., Kawayama, T, Yodoi, J., Kato, S., Iwanaga, T and Aizawa, H. (2007). Effects of thioredoxin on established airway remodeling in a chronic antigen exposure asthma model. Biochem. Biophys. Res. Commun., 360, 525-530 https://doi.org/10.1016/j.bbrc.2007.06.019
  48. Innamorato, N.G., Rojo, AI., Garcia-Yague, AJ., Yamamoto, M., de Ceballos, M.L. and Cuadrado, A (2008). The transcription factor Nrf2 is a therapeutic target against brain inflammation. J. Immunol., 181, 680-689 https://doi.org/10.4049/jimmunol.181.1.680
  49. Ishibashi, N., Prokopenko, O., Reuhl, K.R and Mirochnitchenko, O. (2002). Inflammatory response and glutathione peroxidase in a model of stroke. J. Immunol., 168, 1926-1933 https://doi.org/10.4049/jimmunol.168.4.1926
  50. Ishii, T, Itoh, K., Ruiz, E., Leake, D.S., Unoki, H., Yamamoto, M. and Mann, G.E. (2004). Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. Circulation Res., 94, 609-616 https://doi.org/10.1161/01.RES.0000119171.44657.45
  51. Ishii, Y, Itoh, K., Morishima, Y, Kimura, T, Kiwamoto, T, lizuka, T, Hegab, AE., Hosoya, T, Nomura, A, Sakamoto, T, Yamamoto, M. and Sekizawa, K. (2005). Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J. Immunol., 175, 6968-6975 https://doi.org/10.4049/jimmunol.175.10.6968
  52. Iskander, K., Li, J., Han, S., lheng, B. and Jaiswal, AK. (2006). NQ01 and NQ02 regulation of humoral immunity and autoimmunity. J. Bioi. Chem., 281, 30917-30924 https://doi.org/10.1074/jbc.M605809200
  53. Jaiswal, AK. (2000) Regulation of genes encoding NAD(P)H: quinone oxidoreductases. Free Radic. Bioi. Med., 29, 254-262 https://doi.org/10.1016/S0891-5849(00)00306-3
  54. Jeannin, P., Delneste, Y, Lecoanet-Henchoz, S., Gauchat, J.F., Life, P, Holmes, D. and Bonnefoy, J-Y (1995). Thiols decrease human interleukin (lL) 4 production and IL-4-induced immunoglobulin synthesis. J. Exp. Med., 182, 1785-1792 https://doi.org/10.1084/jem.182.6.1785
  55. Kadl, A, Pontiller, J., Exner, M. and Leitinger, N. (2007). Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia. Shock, 28, 582-588
  56. Karuri, AR., Huang, Y, Bodreddigari, S., Sutter, C.H., Roebuck, B.D., Kensler, TW and Sutter, TR. (2006). 3H-1,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats. J. Pharmacol. Exp. Ther., 317, 61-67 https://doi.org/10.1124/jpet.105.096396
  57. Kataoka, K., Handa, H. and Nishizawa, M. (2001). Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(l) compounds. J. BioI. Chem., 276, 34074-34081 https://doi.org/10.1074/jbc.M105383200
  58. Kawamura, K., Ishikawa, K., Wada, Y, Kimura, S., Matsumoto, H., Kohro, I., Itabe, H., Kodama, I. and Maruyama, Y (2005). Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 155-160
  59. Kensler, T., Waakabayashi, N. and Biswal, S. (2007). Cell survival response to environmental stresses via Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 47, 89-116 https://doi.org/10.1146/annurev.pharmtox.46.120604.141046
  60. Keshavan, P., Deem, TL., Schwemberger, S.J., Babcock, GF., Cook-Mills, J.M. and Zucker, S.D. (2005). Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. J. Immunol., 174, 3709-3718 https://doi.org/10.4049/jimmunol.174.6.3709
  61. Khor, TO., Huang, M.T., Kwon, K.H., Chan, J.Y., Reddy, B.S. and Kong, A.N. (2006). Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res., 66, 11580-11584 https://doi.org/10.1158/0008-5472.CAN-06-3562
  62. Kim, E.-H. and Surh, Y-J. (2006).15-deoxy-${\Delta}^{12,14}$-prostaglandin $J_2$ as a potential endogenous regulator of redox-sensitive transcription factors. Biochem. Pharmacol., 72, 1516-1528 https://doi.org/10.1016/j.bcp.2006.07.030
  63. Kim, J., Cha, Y-N. and Surh, Y-J. (2009). A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat. Res., in press
  64. Kisucka, J., Chauhan, AK., Patten, I.S., Yesilaltay, A., Neumann, C., Van Etten, R.A., Krieger, M. and Wagner, D.D. (2008). Peroxiredoxin1 prevents excessive endothelial activation and early atherosclerosis. Circulation Res., 103, 598-605 https://doi.org/10.1161/CIRCRESAHA.108.174870
  65. Kobayashi, A, Kang, M.I., Okawa, H., Ohtsuji, M., Zenke, Y, Chiba, T., Igarashi, K. and Yamamoto, M. (2004). Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol., 24, 7130-7139 https://doi.org/10.1128/MCB.24.16.7130-7139.2004
  66. Kobayashi, M. and Yamamoto, M. (2005). Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid. Redox Signal., 7, 385-394 https://doi.org/10.1089/ars.2005.7.385
  67. Koike, Y, Hisada, T., Utsugi, M., Ishizuka, T., Shimizu, Y, Ono, A, Murata, Y, Hamuro, J., Mori, M. and Dobashi, K. (2007). Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice. Am. J. Resp. Cell Mol. BioI., 37, 322-329 https://doi.org/10.1165/rcmb.2006-0423OC
  68. Kolls, J.K. (2006). Oxidative stress in sepsis: a redox redux. J. Clin. Investig., 116, 860-863 https://doi.org/10.1172/JCI28111
  69. Kraft, A.D., Lee, J.M., Johnson, D.A., Kan, YW and Johnson, J.A. (2006). Neuronal sensitivity to kainic acid is dependent on the Nrf2-mediated actions of the antioxidant response element. J. Neurochem., 98, 1852-1865 https://doi.org/10.1111/j.1471-4159.2006.04019.x
  70. Lanone, S., Bloc, S., Foresti, R., Almolki, A, Taille, C., Callebert, J., Conti, M., Goven, D., Aubier, M., Dureuil, B., EIBenna, J., Motterlini, R. and Boczkowski, J. (2005). Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J., 19, 1890-1892
  71. Lee, J.M., Chan, K., Kan, YW and Johnson, J.A. (2004). Targeted disruption of Nrf2 causes regenerative immunemediated hemolytic anemia. Proc. Natl. Acad. Sci USA, 101,9751-9756 https://doi.org/10.1073/pnas.0403620101
  72. Lee, J.M. and Johnson, J.A. (2004). An important role of Nrf2-ARE pathway in the cellular defence mechanism. J. Biochem. Mol. BioI., 37, 139-143 https://doi.org/10.5483/BMBRep.2004.37.2.139
  73. Lee, S.H., Sohn, D.H., Jin, X.Y., Kim, S.w., Choi, S.C. and Seo, GS. (2007). 2',4',6'-tris(methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced colitis and blocks tumor necrosis factor-alpha-induced intestinal epithelial inflammation via heme oxygenase 1-dependent and independent pathways. Biochem. Pharmacol., 74, 870-880 https://doi.org/10.1016/j.bcp.2007.06.034
  74. Levonen, A.L., Inkala, M., Heikura, T., Jauhiainen, S., Jyrkkanen, H.K., Kansanen, E., Maatta, K., Romppanen, E., Turunen, P., Rutanen, J. and Yla-Herttuala, S. (2007). Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 741-747 https://doi.org/10.1161/01.ATV.0000258868.80079.4d
  75. Lewis, P., Stefanovic, N., Pete, J., Calkin, AC., Giunti, S., Thallas-Bonke, V., Jandeleit-Dahm, K.A., Allen, TJ., Kola, I., Cooper, M.E. and de Haan, J.B. (2007). Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation, 115, 2178-2187 https://doi.org/10.1161/CIRCULATIONAHA.106.664250
  76. Li, N. and Nel, AE. (2006). Role of the Nrf2-mediated signaling pathway as a negative regulator of inflammation: implications for the impact of particulate pollutants on asthma. Antioxid. Redox Signal., 8, 88-98 https://doi.org/10.1089/ars.2006.8.88
  77. Lin, C.C., Liu, X.M., Peyton, K., Wang, H., Yang, WC., Lin, S.J. and Durante, W (2008). Far infrared therapy inhibits vascular endothelial inflammation via the induction of heme oxygenase-1. Arteriosclerosis, Thrombosis, and Vascular Biology, 28, 739-745 https://doi.org/10.1161/ATVBAHA.107.160085
  78. Liu, X.M., Peyton, K.J., Ensenat, D., Wang, H., Hannink, M., Alam, J. and Durante, W (2007). Nitric oxide stimulates heme oxygenase-1 gene transcription via the Nrf2/ARE complex to promote vascular smooth muscle cell survival. Cardiovasc Res., 75, 381-389 https://doi.org/10.1016/j.cardiores.2007.03.004
  79. Liu, Y, Zhu, B., Wang, X., Luo, L., Li, P., Paty, DW. and Cynader, M.S. (2003). Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J. Neuroimmunol., 139,27-35 https://doi.org/10.1016/S0165-5728(03)00132-2
  80. Ma, Q. and Kinneer, K. (2002). Chemoprotection by phenolic antioxidants. Inhibition of tumor necrosis factor alpha induction in macrophages. J. BioI. Chem., 277, 2477-2484 https://doi.org/10.1074/jbc.M106685200
  81. Ma, Q., Battelli, L. and Hubbs, A.F. (2006). Multiorgan autoimmune inflammation, enhanced Iymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am. J. Pathol., 168, 1960-1974 https://doi.org/10.2353/ajpath.2006.051113
  82. Manna, S.K., Kuo, M.T. and Aggarwal, B.B. (1999). Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1. Oncogene, 18, 4371-4382 https://doi.org/10.1038/sj.onc.1202811
  83. Manna, SK, Mukhopadhyay, A and Aggarwal, B.B. (2000). Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol., 164, 6509-6519 https://doi.org/10.4049/jimmunol.164.12.6509
  84. Marzec, J.M., Christie, J.D., Reddy, S.P., Jedlicka, AE., Vuong, H., Lanken, P.N., Aplenc, R, Yamamoto, 1., Yamamoto, M., Cho, H.Y. and Kleeberger, S.R. (2007). Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J., 21, 2237-2246 https://doi.org/10.1096/fj.06-7759com
  85. Matthews, GM. and Butler, RN. (2005). Cellular mucosal defense during Helicobacter pylori infection: a review of the role of glutathione and the oxidative pentose pathway. Helicobacter, 10, 298-306 https://doi.org/10.1111/j.1523-5378.2005.00327.x
  86. Mirochnitchenko, O., Prokopenko, O., Palnitkar, U., Kister, I., Powell, WS. and Inouye, M. (2000). Endotoxemia in transgenic mice overexpressing human glutathione peroxidases. Circulation Res., 87, 289-295 https://doi.org/10.1161/01.RES.87.4.289
  87. Misso, N.L., Powers, K.A., Gillon, RL., Stewart, GA and Thompson, PJ. (1996). Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients. Clin. Exp. Allergy, 26, 838-847 https://doi.org/10.1111/j.1365-2222.1996.tb00616.x
  88. Mochizuki, M., Ishii, Y, Itoh, K., lizuka, T., Morishima, Y, Kimura, T., Kiwamoto, T., Matsuno, Y, Hegab, AE., Nomura, A, Sakamoto, T., Uchida, K., Yamamoto, M. and Sekizawa, K. (2005). Role of 15_deoxy_${\Delta}^{12,14}$ prostaglandin $J_2$ and Nrf2 pathways in protection against acute lung injury. Am. J. Respir. Critical Care Medicine, 171, 1260-1266 https://doi.org/10.1164/rccm.200406-755OC
  89. Moutet, M., d'Alessio, P., Malette, P, Devaux, V. and Chaudiere, J. (1998). Glutathione peroxidase mimics prevent TNFalpha-and neutrophil-induced endothelial alterations. Free Radic. Bioi. Med., 25, 270-281 https://doi.org/10.1016/S0891-5849(98)00038-0
  90. Murakami, A, Matsumoto, K., Koshimizu, K. and Ohigashi, H. (2003). Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon-gamma-induced IkappaB degradation in RAW264.7 macrophages. Cancer Letters, 195, 17-25 https://doi.org/10.1016/S0304-3835(03)00058-2
  91. Murata, Y, Shimamura, T. and Hamuro, J. (2002a). The polarization of T(h)11T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Intl. Immunol., 14, 201-212 https://doi.org/10.1093/intimm/14.2.201
  92. Murata, Y, Amao, M., Yoneda, J. and Hamuro, J. (2002b). Intracellular thiol redox status of macrophages directs the Th1 skewing in thioredoxin transgenic mice during aging. Mol. Immunol., 38, 747-757 https://doi.org/10.1016/S0161-5890(01)00111-0
  93. Na, H.-K. and Surh, Y-J. (2006). Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection. Mol. Carcinog., 45, 368-380 https://doi.org/10.1002/mc.20225
  94. Nakamura, A, Mori, Y, Hagiwara, K., Suzuki, T., Sakakibara, T., Kikuchi, T., Igarashi, T., Ebina, M., Abe, T., Miyazaki, J., Takai, T. and Nukiwa, T. (2003). Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. J. Exp. Med., 197, 669-674 https://doi.org/10.1084/jem.20021824
  95. Nagai, N., Thimmulappa, R.K., Cano, M., Fujihara, M., IzumiNagai, K., Kong, X., Sporn, M.B., Kensler, TW, Biswal, S. and Handa, J.T. (2009). Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic. BioI. Med., 47, 300-306 https://doi.org/10.1016/j.freeradbiomed.2009.04.033
  96. Nakamura, Y, Feng, Q., Kumagai, T., Torikai, K., Ohigashi, H., Osawa, T., Noguchi, N., Niki, E. and Uchida, K. (2002). Ebselen, a glutathione peroxidase mimetic selenoorganic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis. J. Biol. Chem., 277, 2687-2694 https://doi.org/10.1074/jbc.M109641200
  97. Niki, E. (1997). Mechanisms and dynamics of antioxidant action of ubiquinol. Molecular Aspects of Medicine, 18 Suppl, S63-70 https://doi.org/10.1016/S0098-2997(97)00035-6
  98. Ohashi, S., Nishio, A, Nakamura, H., Asada, M., Tamaki, H., Kawasaki, K., Fukui, T., Yodoi, J. and Chiba, . (2006). Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. Antioxidants & Redox Signaling, 8, 1835-1845 https://doi.org/10.1089/ars.2006.8.1835
  99. Ortolani, O., Conti, A, De Gaudio, AR, Moraldi, E. and Novelli, GP. (2002). [Glutathione and N-acetylcysteine in the prevention of free-radical damage in the initial phase of septic shock]. Recent Prog. Med., 93, 125-129
  100. Osburn, WO., Karim, B., Dolan, P.M., Liu, G, Yamamoto M., Huso, D.L. and Kensler, TW (2007). Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. Int. J. Cancer., 121,1883-1891 https://doi.org/10.1002/ijc.22943
  101. Overhaus, M., Moore, B.A., Barbato, J.E., Behrendt, F.F., Doering, J.G and Bauer, AJ. (2006). Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. Am. J. Physiol. Gastrointest. Liver Physiol., 290, G695-703 https://doi.org/10.1152/ajpgi.00152.2005
  102. Pae, H.O., Ae Ha, Y, Chai, K.Y. and Chung, H.T. (2008). Heme oxygenase-1 attenuates contact hypersensitivity induced by 2,4-dinitrofluorobenzene in mice. Immunopharmacol. Immunotoxicol., 30, 207-216 https://doi.org/10.1080/08923970801946824
  103. Pae, H.O., Oh, GS., Lee, B.S., Rim, J.S., Kim, YM. and Chung, H.T. (2006). 3-Hydroxyanthranilic acid, one of Ltryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis, 187, 274-284 https://doi.org/10.1016/j.atherosclerosis.2005.09.010
  104. Pang, R, Zhang, S.L., Zhao, L., Liu, S.L., Dong, J.H. and Tao, J.Y. (2008). Effect of petroleum ether extract from Melilotus suaveolens Ledeb on the expression of NF-kappaB and Heme oxygenase 1. Xi Baa Yu Fen Zi Mian Yi Xue Za Zhi, 24, 861-863
  105. Parsons, M.S., Barrett, L., Little, C. and Grant, M.D. (2008). Harnessing CD36 to rein in inflammation. Endocr, Metab. Immune Disord. Drug Targets, 8, 184-191 https://doi.org/10.2174/187153008785700073
  106. Patil, K., Bellner, L., Cullaro, G, Gotlinger, K.H., Dunn, M.W. and Schwartzman, M.L. (2008). Heme oxygenase-1 induction attenuates corneal inflammation and accelerates wound healing after epithelial injury. Invest. Ophthalmol. Vis. Sci., 49, 3379-3386 https://doi.org/10.1167/iovs.07-1515
  107. Peran, L., Camuesco, D., Comalada, M., Nieto, A., Concha, A., Adrio, J.L., Olivares, M., Xaus, J., Zarzuelo, A. and Galvez, J. (2006). Lactobacillus fermentum, a probiotic capable to release glutathione, prevents colonic inflammation in the TNBS model of rat colitis. Int. J. Color ectal Dis., 21, 737-746 https://doi.org/10.1007/s00384-005-0773-y
  108. Peterson, J.D., Herzenberg, L.A., Vasquez, K. and Waltenbaugh, C. (1998). Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc. Natl. Acad. Sci. USA, 95, 3071-3076 https://doi.org/10.1073/pnas.95.6.3071
  109. Rahman, I. (2005). Regulation of glutathione in inflammation and chronic lung diseases. Mutat. Res., 579, 58-80 https://doi.org/10.1016/j.mrfmmm.2005.02.025
  110. Rahman, I. and MacNee, W (2000). Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic. BioI. Med., 28, 1405-1420 https://doi.org/10.1016/S0891-5849(00)00215-X
  111. Rangasamy, T, Cho, C.Y., Thimmulappa, RK., Zhen, L., Srisuma, S.S., Kensler, TW, Yamamoto, M., Petrache, I., Tuder, RM. and Biswal, S. (2004). Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J. Clin. Investig., 114, 1248-1259 https://doi.org/10.1172/JCI200421146
  112. Rangasamy, T, Guo, J., Mitzner, WA., Roman, J., Singh, A., Fryer, A.D., Yamamoto, M., Kensler TW, Tuder, RM., Georas, S.N. and Biswal, S. (2005). Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med., 202, 47-59 https://doi.org/10.1084/jem.20050538
  113. Reddy, N.M., Suryanarayana, V., Kalvakolanu, DV, Yamamoto, M., Kensler, TW, Hassoun, P.M., Kleeberger, S.R. and Reddy, S.P (2009). Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice. J. Immunol., 183, 4601-4608 https://doi.org/10.4049/jimmunol.0901754
  114. Ritz, SA, Wan, J. and Diaz-Sanchez, D. (2007). Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract. Am. J. Physiol. Lung Cell Mol. Physiol., 292, L33-39
  115. Romagnani, S. (1994). Lymphokine production by human T cells in disease states. Annu. Rev. Immunol., 12, 227-257 https://doi.org/10.1146/annurev.iy.12.040194.001303
  116. Ross, D. (2004). Quinone reductases multitasking in the metabolic world. Drug Metab. Rev., 36, 639-654 https://doi.org/10.1081/DMR-200033465
  117. Ross, D., Kepa, J.K., Winski, S.L., Beall, H.D., Anwar, A. and Siegel, D. (2000). NAD(P)H:quinone oxidoreductase 1 (NQ01): chemoprotection, bioactivation, gene regulation and genetic polymorph isms. Chem.-Biological. interactions, 129, 77-97 https://doi.org/10.1016/S0009-2797(00)00199-X
  118. Ross, R (1999). Atherosclerosis--an inflammatory disease. New England J. Med., 340, 115-126 https://doi.org/10.1056/NEJM199901143400207
  119. Roth, M. and Black, J.L. (2006). Transcription factors in asthma: are transcription factors a new target for asthma therapy? Current Drug Targets, 7, 589-595 https://doi.org/10.2174/138945006776818638
  120. Roum, J.H., Borok, Z., McElvaney, N.G, Grimes, G.J., Bokser, A.D., Buhl, R and Crystal, RG (1999). Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J. Appl. Physiol., 87,438-443
  121. Sarady-Andrews, J.K., Liu, F., Gallo, D., Nakao, A., Overhaus, M., Ollinger, R., Choi, A.M. and Otterbein, L.E. (2005). Biliverdin administration protects against endotoxin-induced acute lung injury in rats. Am. J. Physiol. Lung Cell. Mol. Physiol., 289, L1131-1137 https://doi.org/10.1152/ajplung.00458.2004
  122. Sato, A., Hoshino, Y, Hara, T, Muro, S., Nakamura, H., Mishima, M. and Yodoi, J. (2008). Thioredoxin-1 ameliorates cigarette smoke-induced lung inflammation and emphysema in mice. J. Pharmacol. Exp. Ther., 325, 380-388 https://doi.org/10.1124/jpet.107.134007
  123. Sawada, K., Ohnishi, K., Kosaka, T, Chikano, S., Egashira, A., Okui, M., Shintani, S., Wada, M., Nakasho K. and Shimoyama, T (1997). Exacerbated autoimmune hepatitis successfully treated with leukocytapheresis and bilirubin adsorption therapy. J. Gastroenterol., 32, 689-695 https://doi.org/10.1007/BF02934123
  124. Seldon, M.P., Silva, G, Pejanovi,c N., Larse,n R, Gregoire, I.P, Filipe, J., Anrather, J. and Soares, M.P (2007). Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation at serine 276. J. Immunol., 179, 7840-7851 https://doi.org/10.4049/jimmunol.179.11.7840
  125. Shen, X.D., Ke, B., Zhai, Y, Gao, F., Busuttil, RW, Cheng, G and Kupiec-Weglinski, J.W (2005). Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am. J. Transplant., 5, 1793-1800 https://doi.org/10.1111/j.1600-6143.2005.00932.x
  126. Srisook, K., Kim, C. and Cha, YN. (2005). Molecular mechanisms involved in enhancing HO-1 expression: de-repression by heme and activation by Nrf2, the 'one-two' punch. Antioxidants & Redox Signaling, 7, 1674-1687 https://doi.org/10.1089/ars.2005.7.1674
  127. Steinberg, D. (1997). Low density lipoprotein oxidation and its pathobiological significance. J. BioI. Chem., 272, 20963-20966 https://doi.org/10.1074/jbc.272.34.20963
  128. Steinbrecher, U.P (1999). Receptors for oxidized low density lipoprotein. Biochim. Biophys. Acta, 1436, 279-298 https://doi.org/10.1016/S0005-2760(98)00127-1
  129. Sun, B., Zou, X., Chen, Y, Zhang, P and Shi, G (2008a). Preconditioning of carbon monoxide releasing moleculederived CO attenuates LPS-induced activation of HUVEC. Int. J. BioI. Sci., 4, 270-278
  130. Sun, B.W, Sun, Y, Sun, Z.W and Chen, X. (2008b). CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice. World J. Gastroenterol., 14, 547-553 https://doi.org/10.3748/wjg.13.6127
  131. Sun, J., Hoshino, H., Takaku, K., Nakajima, 0., Muto, A., Suzuki, H., Tashiro, S., Takahashi, S., Shibahara, S., Alam, J., Taketo, M.M., Yamamoto, M. and Igarashi, K. (2002). Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J., 21, 5216-5224 https://doi.org/10.1093/emboj/cdf516
  132. Sun, S., Zhang, H., Xue, B., Wu, Y, Wang, J., Yin, Z. and Luo, L. (2006). Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats. Inflamm. Res., 55, 504-510 https://doi.org/10.1007/s00011-006-6037-7
  133. Syapin, PJ. (2008). Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br. J. Pharmacol., 155,623-640 https://doi.org/10.1038/bjp.2008.342
  134. Tamaki, H., Nakamura, H., Nishio, A., Nakase, H., Ueno, S., Uza, N., Kido, M., Inoue, S., Mikami, S., Asada, M., Kiriya, K., Kitamura, H., Ohashi, S., Fukui, T, Kawasaki, K., Matsuura, M., Ishii, Y, Okazaki, K., Yodoi, J. and Chiba, T (2006). Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production. Gastroenterology, 131, 1110-1121 https://doi.org/10.1053/j.gastro.2006.08.023
  135. Tamion, F., Richard, V, Renet, S. and Thuillez, C. (2007). Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model. Am, J. Physiol. Gastrointest. Liver Physiol., 293, G1308-1314 https://doi.org/10.1152/ajpgi.00154.2007
  136. Thimmulappa, RK., Lee, H., Rangasamy, T, Reddy, S.P, Yamamoto, M., Kensler, TW and Biswal, S. (2006). Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J. Clin. Investig., 116, 984-995 https://doi.org/10.1172/JCI25790
  137. Tirouvanziam, R., Conrad, C.K., Bottiglieri, T, Herzenberg, LA and Moss, RB. (2006). High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc. Natl. Acad. Science USA, 103, 4628-4633 https://doi.org/10.1073/pnas.0511304103
  138. Tsuchihashi, S., Zhai, Y, Bo, Q., Busuttil, RW and KupiecWeglinski, J.W (2007). Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling. Transplantation, 83, 1628-1634 https://doi.org/10.1097/01.tp.0000266917.39958.47
  139. Tsuji, G, Koshiba, M., Nakamura, H., Kosaka, H., Hatachi, S., Kurimoto, C., Kurosaka, M., Hayashi, Y, Yodoi, J. and Kumagai, S. (2006). Thioredoxin protects against joint destruction in a murine arthritis model. Free Radic. Bioi. Med., 40,1721-1731 https://doi.org/10.1016/j.freeradbiomed.2006.01.006
  140. Venugopal, Rand Jaiswal, AK. (1996). Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl. Acad. Sci. USA, 93, 14960-14965 https://doi.org/10.1073/pnas.93.25.14960
  141. Villa, P., Saccani, A, Sica, A and Ghezzi, P. (2002). Glutathione protects mice from lethal sepsis by limiting inflammation and potentiating host defense . . J Infect. Dis., 185,1115-1120 https://doi.org/10.1086/340042
  142. Wagener, FA, Volk, H.D., Willis, D., Abraham, N.G, Soares, M.P., Adema, GJ. and Figdor, C.G (2003). Different faces of the heme-heme oxygenase system in inflammation. Pharmacal. Rev., 55, 551-571 https://doi.org/10.1124/pr.55.3.5
  143. Wang, J., Fields, J., Zhao, C., Langer, J., Thimmulappa, RK., Kensler, TW, Yamamoto, M., Biswal, S. and Dore, S. (2007). Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic. Bioi. Med., 43, 408-414 https://doi.org/10.1016/j.freeradbiomed.2007.04.020
  144. Wang, Wand Jaiswal, AK. (2006). Nuclear factor Nrf2 and antioxidant response element regulate NRH:quinone oxidoreductase 2 (NQ02) gene expression and antioxidant induction. Free Radic. BioI. Med., 40, 1119-1130 https://doi.org/10.1016/j.freeradbiomed.2005.10.063
  145. Wang, WW, Smith, D.L. and Zucker, S.D. (2004). Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats. Hepatology, 40, 424-433 https://doi.org/10.1002/hep.20334
  146. Xia, Z.W, Xu, L.Q., Zhong, WW, Wei, J.J., Li, N.L., Shao, J., Li, YZ., Yu, S.C. and Zhang, Z.L. (2007). Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-1. Am. J. Pathol., 171, 1904-1914 https://doi.org/10.2353/ajpath.2007.070096
  147. Yachie, A, Toma, T, Mizuno, K., Okamoto, H., Shimura, S., Ohta, K., Kasahara, Y and Koizumi, S. (2003). Heme oxygenase-1 production by peripheral blood monocytes during acute inflammatory illnesses of children. Exp. Bioi. Med. (Maywood), 228, 550-556
  148. Yang, C.S., Lee, D.S., Song, C.H., An, S.J., Li, S., Kim, J.M., Kim, CS., Yoo, D.G, Jeon, B.H., Yang, HY, Lee, TH., Lee, Z.W, EI-Benna, J., Yu, DY and Jo, E.K. (2007). Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxininduced lethal shock. J. Exp.l Med., 204, 583-594 https://doi.org/10.1084/jem.20061849
  149. Yoh, K., Itoh, K., Enomoto, A, Hirayama, A, Yamaguchi, N., Kobayashi, M., Morito, N., Koyama, A, Yamamoto, M. and Takahashi, S. (2001). Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Intemational, 60, 1343-1353 https://doi.org/10.1046/j.1523-1755.2001.00939.x
  150. Zabalgoitia, M., Colston, J.T., Reddy, S.v., Holt, J.W, Regan, RF., Stec, D.E., Rimoldi, J.M., Valente, AJ. and Chandrasekar, B. (2008). Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death. Free Radic. Bioi. Med., 44, 284-298 https://doi.org/10.1016/j.freeradbiomed.2007.08.012
  151. Zhang, F., Wang, X., Wang, W, Li, N. and Li, J. (2008). Glutamine reduces tnf-alpha by enhancing glutathione synthesis in lipopolysaccharide-stimulated alveolar epithelial cells of rats. Inflammation, 31, 344-350 https://doi.org/10.1007/s10753-008-9084-0
  152. Zhang, X., Lu, L., Dixon, C., Wilmer, W, Song, H., Chen, X. and Rovin, B.H. (2004). Stress protein activation by the cyclopentenone prostaglandin 15-deoxy-delta12,14-prostaglandin J2 in human mesangial cells. Kidney Intemational, 65, 798-810 https://doi.org/10.1111/j.1523-1755.2004.00454.x
  153. Zhao, X., Sun, G, Zhang, J., Strong, R, Dash, PK., Kan, YW, Grotta, J.C. and Aronowski, J. (2007). Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke, 38, 3280-3286 https://doi.org/10.1161/STROKEAHA.107.486506
  154. Zhu, M., Zhang, Y, Cooper, S., Sikorski, E., Rohwer, J. and Bowden, GT (2004). Phase II enzyme inducer, sulforaphane, inhibits UVB-induced AP-1 activation in human keratinocytes by a novel mechanism. Mol. Carcinog., 41, 179-186 https://doi.org/10.1002/mc.20052