NF-κB in liver diseases: A target for drug therapy

Journal of Applied Toxicology

Volumn 29, Issue 2, 2009, Pages 91-100

  Muriel, Pablo ^a  

^a DEPARTAMENTO DE FÍSICA   (Mexico)

Author keywords

Caffeic acid; Cancer; Captopril; Curcumin; Liver damage; NF B; Pyrrolidine dithiocarbamate; Resveratrol; Silymarin; Thalidomide

Indexed keywords

CAFFEIC ACID; CAPTOPRIL; CURCUMIN; HOMODIMER; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 10; INTERLEUKIN 6; PARACETAMOL; PROTEIN P50; PROTEIN SUBUNIT; PYRROLIDINE DITHIOCARBAMATE; RESVERATROL; SCATTER FACTOR; SILYMARIN; THALIDOMIDE; TRANSCRIPTION FACTOR REL;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CHOLESTASIS; CHRONIC LIVER DISEASE; CYTOKINE PRODUCTION; DRUG TARGETING; GENE EXPRESSION; HEPATITIS; HUMAN; IN VIVO STUDY; INNATE IMMUNITY; KUPFFER CELL; LIVER CELL CARCINOMA; LIVER DISEASE; LIVER FIBROSIS; LIVER INJURY; LIVER REGENERATION; NECROSIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; TUMOR PROMOTION; UPREGULATION; ANIMAL; BIOLOGICAL MODEL; DRUG EFFECT; FIBROSIS; IMMUNOLOGY; INFLAMMATION; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; APOPTOSIS; FIBROSIS; HUMANS; IMMUNITY, INNATE; INFLAMMATION; INTERLEUKIN-6; LIVER DISEASES; MODELS, BIOLOGICAL; NF-KAPPA B; UP-REGULATION;

EID: 62849092266     PISSN: 0260437X     EISSN: 10991263     Source Type: Journal    
DOI: 10.1002/jat.1393     Document Type: Review

References (152)

1. Abe Y, Hashimoto S, Hori T. 1999. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol. Res. 39: 41-47.
2. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishoda S, Takada Y. 2004. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 24: 2783-2840.
3. Ammon HP, Wahl MA. 1991. Pharmacology of Curcuma longa. Planta Med. 57: 1-7.
4. Anderson CF, Mosser DM. 2002. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J. Immunol. 168: 3697-3701.
5. Arsura M, Cavin LG. 2005. Nuclear factor-κB and liver carcinogenesis. Cancer Lett. 229: 157-169.
6. Baer M, Dillner A, Schwartz RC, Sedon C, Nedospasov S, Johnson PF. 1998. Tumor necrosis factor alpha transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-κB p50. Mol. Cell Biol. 18: 5678-5689.
7. Barón V, Muriel P. 1999. Role of glutathione, lipid peroxidation and antioxidants on acute bile duct obstruction in the rat. Biochim. Biophys. Acta. 1472: 173-180.
8. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. 1995. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376: 167-170.
9. Benkhart EM, Siedlar M, Wedel A, Werner T, Ziegler-Heit-brok HW. 2000. Role of Stat 3 in lipopolysaccharide-induced IL-10 gene expression. J. Immunol. 165: 1612-1617.
10. Boot JR, Kitchen EA, Walker JR, Harvey J, Dawson W. 1985. Directional movement of cells in vivo and in vitro under the influence of 5-lipoxygenase inhibitors. Br. J. Dermatol. 113: 168-173.
11. Brightbill HD, Plevy SE, Modlin RL, Smale ST. 2000. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J. Immunol. 164: 1940-1951.
12. Bruck R, Aeed H, Schey R, Matas Z, Reifen R, Zaiger G, Hochman A, Avni Y. 2002. Pyrrolidine dithiocarbamate protects against thioacetamide-induced fulminant hepatic failure in rats. J. Hepatol. 36: 370-377.
13. Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines M. 2004. A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver Int. 24: 169-176.
14. Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H, Genina O, Helpern Z, Pines M. 2007. Prevention of liver cirrhosis in rats by curcumin. Liver Int. 27: 373-383.
15. Cao S, Liu J, Song L, Ma X. 2005. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J. Immunol. 174: 3484-3492.
16. Cao S, Zhang X, Edwards JP, Mosser DM. 2006. NF-κB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. J. Biol. Chem. 281: 26041-26050.
17. Carcache de-Blanco EJ, Pandit B, Hu Z, Shi J, Lewis A, Li PK. 2007. Inhibitors of NF-κB derived from thalidomide. Bioorg. Med. Chem. Lett. 17: 6031-6031.
18. Chaisson ML, Brooling JT, Ladiges W, Tsai S, Fausto N. 2002. Hepatocyte-specific inhibition of NF-κB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J. Clin. Invest. 110: 193-202.
19. Chan CF, Yau TO, Jin DY, Wong CM, Fan ST, Ng IO. 2004. Evaluation of nuclear factor-κB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma. Clin. Cancer Res. 10: 4140-4149.
20. 4-induced cirrhosis. Toxicol. Mech. Meth. 16: 507-513.
21. 4 treatment in rats. J. Appl. Toxicol. 28: 35-43.
22. Cintra DE, Pauli JR, Araujo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, Velloso LA. 2008. Interleukin-10 is protective factor against diet-induced insulin resistance in liver. J. Hepatol. 48: 628-637.
23. Conti P, Kempuraj D, Frydas S, Kandere K, Boucher W, Letourneau R, Madhappan B, Sagimoto K, Christodoulou S, Theoharides TC. 2003. Interleukin 10 subfamily members: IL-19, IL-20, IL-22, IL-24, IL-26. Immunol. Lett. 88: 171-174.
24. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R. 1996. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274: 1379-1383.
25. DeAngelis RA, Kovalovich K, Cressman DE, Taub R. 2001. Normal liver regeneration in p50/nuclear factor κB1 knockout mice. Hepatology 33: 915-924.
26. Den Boer MA, Voshol PJ, Schroder-van der Elst JP, Korsheninnikova E, Ouwens DM, Kuipers F, Havekes LM, Romijn JA. 2006. Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high fat feeding in mice. Endocrinology 147: 4553-4558.
27. Deng WG, Wu KK. 2003. Regulation of inducible nitric oxide synthase expression by p300 and p50 acetylation. J. Immunol. 171: 6581-6588.
28. Dhanalakshmi S, Singh RP, Agarwal C, Agarwal R. 2002. Silibinin inhibits constitutive and TNF α-induced activation of NF-κB and sensitizes human prostate carcinoma DU145 cells to TNF α-induced apoptosis. Oncogene 21: 1759-1767.
29. Dinant S, Veteläinen RL, Florquin S, van Vliet AK, van Gulik TM. 2007. IL-10 attenuates hepatic I/R injury and promotes hepatocyte proliferation. J. Surg. Res. 141: 176-182.
30. Dong Z. 2003. Molecular mechanisms of the chemopreventive effect of resveratrol. Mutat. Res. 523: 145-150.
31. Edwards MJ, Keller BJ, Kauffman FC, Thurman RG. 1993. The involvement of Kupffer cells in carbon tetrachloride toxicity. Toxicol. Appl. Pharmacol. 119: 275-279.
32. Elsharkawy AM, Mann DA. 2007. Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46: 590-597.
33. Erhart A, Biburger M, Papadopoulos T, Tiegs G. 2007. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45: 475-485.
34. Faubion W, Guicciardi M, Miyoshi H, Bronk S, Roberts P, Svingen P, Kaufmann S, Gores G. 1999. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J. Clin. Invest. 103: 137-145.
35. Fauconneau B, Waffo-Teguo P, Huguet F, Barrier L, Decendit A, Merillon JM. 1997. Comparative study of radical scavenger and antioxidant properties of phenolic compounds from Vitis vinifera cell cultures using in vitro tests. Life Sci. 61: 2103-2110.
36. Fausto N. 2000. Liver regeneration. J. Hepatol. 32: 19-31.
37. Fernández-Martínez E, Bobadilla RA, Morales-Ríos MS, Muriel P, Pérez-Álvarez VM. 2007. Trans-3-phenyl-2-propenoic acid (Cinnamic Acid) derivatives: structure-activity relationship as hepatoprotective agents. Med. Chem. 3: 475-479.
38. Fernández-Martínez E, Morales-Ríos MS, Pérez-Álvarez V, Muriel P. 2001. Effects of thalidomide and 3-phthalimido-3-(3,4-dimethoxyphenyl)-propanamide on bile duct obstruction-induced cirrhosis in the rat. Drug Dev. Res. 54: 209-218.
39. Fernández-Martínez E, Morales-Ríos MS, Pérez-Álvarez V, Muriel P. 2004. Immunomodulatory effects of thalidomide analogs on LPS-induced plasma and hepatic cytokines in the rat. Biochem. Pharmacol. 68: 1321-1329.
40. Fernández-Martínez E, Pérez-Álvarez V, Tsutsumi V, Shibayama M, Muriel P. 2006. Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat. Exp. Toxicol. Pathol. 58: 49-58.
41. Fickenscher H, Hor S, Kupers H, Knappe A, Wittmann S, Sticht H. 2002. The interleukin-10 family of cytokines. Trends Immunol. 23: 89-96.
42. Freemont L. 2000. Biological effects of resveratrol. Life Sci. 66: 663-673.
43. Fujita T, Nolan GP, Liou HC, Scott ML, Baltimore D. 1993. The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-κB p50 homodimers. Genes Dev. 7: 1354-1363.
44. Fujiwara N, Kobayashi K. 2005. Macrophages in inflammation. Curr. Drug Targets Inflamm. Allergy 4: 281-286.
45. Gale RP, Sparkes RS, Golde DW. 1978. Bone marrow origin of hepatic macrophages (Kupffer cells) in humans. Science 201: 937-938.
46. Gallois C, Habib A, Tao J, Moulin S, Maclouf J, Mallat A, Lotersztajn S. 1998. Role of NF-kappa B in the antiproliferative effect of endotelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2. J. Biol. Chem. 273: 23183-23190.
47. Gerondakis S, Grossmann M, Nakamura Y, Pohl T, Grumont R. 1999. Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts. Oncogene 18: 6888-6895.
48. Ghosh S, May MJ, Kopp EB. 1998. NF-kappa B and Rel proteins: evolutionary conserved mediators of immune responses. A. Rev. Immunol. 16: 225-260.
49. Grütz G. 2005. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J. Leuc. Biol. 77: 3-15.
50. Gupta S, Young D, Sen S. 2005. Inhibition of NF-kappaB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. Am. J. Physiol. Heart Circul. Physiol. 289: H17-19.
51. Hasuike S, Ido A, Uto H, Moriuchi A, Tahara Y, Numata M, Nagata K, Hori T, Hayashi K, Tsubouchi H. 2005. Hepatocyte growth factor accelerates the proliferation of hepatic oval cells and possibly promotes the differentation in a 2-acetylaminofluorene/partial hepatectomy model in rats. J. Gastroenterol. Hepatol. 20: 1753-1761.
52. Hellerbrand C, Jobin C, Licato LL, Sartor RB, Brenner DA. 1998a. Cytokines induce NF-kappa B in activated but in quiescent rat hepatic stellate cells. Am. J. Physiol. 275: G269-G278.
53. Hellerbrand C, Jobin C, Limuro Y, Licato LL, Sartor RB, Brenner DA. 1998b. Inhibition of NF-kappa B in activated rat stellate cells by proteasome inhibitors and an I-kappa B super-repressor. Hepatology 27: 1285-1295.
54. Hellerbrand C, Wang SC, Tsukamoto H, Brenner DA, Rippe RA. 1996. Expression of intracellular adhesion molecule 1 by activated hepatic stellate cells. Hepatology 24: 670-676.
55. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. 2004. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl Acad. Sci. USA 101: 4477-4482.
56. Husztzik E, Lázár G, Párduc A. 1980. Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br. J. Exp. Pathol. 61: 624-630.
57. Iimuro Y, Nishiura T, Hellerbrand C, Behrns KE, Schoonhoven R, Grisham JW, Brenner DA. 1998. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest. 108: 802-811.
58. Johnson C, Van Antiver D, Hope TJ. 1999. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of I kappaBelpha. EMBO J. 18: 6682-6693.
59. Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, Purdie DM, Powell EE. 2001. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 121: 148-155.
60. Kaisho T, Akira S. 2000. Critical roles of toll-like receptors in host defense. Crit. Rev. Immunol. 20: 393-405.
61. Kaplan DE, Ikeda F, Li Y, Nakamoto N, Ganesan S, Valiga ME, Nunes FA, Rajender Reddy K, Chang KM. 2008. Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis. J. Hepatol. 48: 903-913.
62. Karin M. 2008. The IκB kinase - a bridge between inflammation and cancer. Cell Res. 18: 334-342.
63. Karin M, Lin A. 2002. NF-kappaB at the crossroads of life and death. Nat. Immunol. 3: 221-227.
64. Karin M, Cao Y, Greten FR, Li ZW. 2002. NF-κB in cancer: from innocent bystander to major culprit. Natl Rev. Cancer 2: 301-310.
65. Kato A, Edwards MJ, Lentsch AB. 2002. Gene deletion of NF-κB p50 does not alter the hepatic inflammatory response to ischemia/reperfusion. J. Hepatol. 37: 34-55.
66. Kawada N, Seki S, Inoue M, Kuroki T. 1998. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 27: 1265-1274.
67. Kirillova I, Chaisson M, Fausto N. 1999. Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor kappaB activation. Cell Growth Differ. 10: 819-828.
68. Knolle P, Schlaak J, Urig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G. 1995. Human Kupffer cells secrete IL-10 in response to lipolysacharide (LPS) challenge. J. Hepatol. 22: 226-229.
69. Laskin DL. 1990. Nonparenchymal cells and hepatotoxicity. Semin. Liver Dis. 10: 293-304.
70. Lavon I, Goldberg I, Amit S, Lansman I, Jung S, Tsuberi BZ, Barshack I, Kopolovic J, Galun E, Bujard H, Ben-Neriah Y. 2000. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nat. Med. 6: 573-577.
71. Lawrence T, Gilroy DW, Colvielle-Nash PR, Willoughby DA. 2001. Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7: 1291-1297.
72. Lee KS, Buck M, Houglum K, Chojkier M. 1995. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myc expression. J. Clin. Invest. 96: 2461-2468.
73. Le Moine O, Marchant A, De Groote D, Azar C, Goldman M, Devière J. 1995. Role of the effective monocyte interleukin-10 release in tumor necrosis factor-alpha overproduction in alcoholic cirrhosis. Hepatology 22: 1436-1439.
74. Li Q, Verma IM. 2002. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2: 725-734.
75. Li Y, Schwabe RF, De Vries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I. 2005. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J. Biol. Chem. 280: 21763-21772.
76. Lin SC. 2006. Identification of an NF-γ/HMG-I(γ)-binding site in the human IL-10 promoter. Mol. Immunol. 43: 1325-1331.
77. Liu YW, Tseng HP, Chen LC, Chen BK, Chang WC. 2003. Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein beta and delta in lipopolysaccaride-induced gene activation of IL-10 in mouse macrophages. J. Immunol. 171: 821-828.
78. Loughran PA, Stolz DB, Vodovotz Y, Watkins SC, Simmons RL, Billiar TR. 2005. Monomeric inducible nitric oxide synthase localizes to peroxisomes in hepatocytes. Proc. Natl Acad. Sci. USA 102: 13837-13842.
79. Louis H, Le Moine O, Peny MO, Quertinmont E, Fokan D, Goldman M, Devière J. 1997. Production and role of interleukin-10 in concanavalin A-induced hepatitis in mice. Hepatology 25: 1382-1389.
80. Lucas M, Zhang X, Prasanna V, Mosser DM. 2005. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175: 469-477.
81. Luedde T, Assmus U, Wustefeld T, Meyer zu Vilsendorf A, Roskams T, Schmidt-Supprian M, Rajewsky K, Brenner DA, Manns MP, Pasparakis M, Trautwein C. 2005. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. J. Clin. Invest. 115: 849-859.
82. Luedde T, Beraza N, Kotsikoris V, van LG, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M. 2007. Deletion of NEMO/IKKgamma in liver parenchyma cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11: 119-132.
83. Luo JL, Kamata H, Karin M. 2005. The anti-death machinery in IKK/NFkappaB signaling. J. Clin. Immunol. 25: 541-550.
84. Mackay IR. 2002. Hepatoimmunology: a perspective. Immunol. Cell Biol. 80: 36-44.
85. Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M. 2003. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNF alpha. Immunity 19: 725-737.
86. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. 2005. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121: 977-990.
87. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. 2006. Multiple biological activities of curcumin: a short review. Life Sci. 78: 2081-2087.
88. Manna SK, Mukhpadhyay A, Van NT, Aggarwal BB. 1999. Silymarin suppresses TNF-induced activation of NF-kappa B, C-Jun N-terminal kinase, and apoptosis. J. Immunol. 163: 6800-6809.
89. Marienfeld R, May MJ, Berberich I, Serling E, Ghosh S, Newmann M. 2003. RelB forms transcriptionally inactive complexes with RelA/p65. J. Biol. Chem. 278: 19852-19860.
90. Miyoshi H, Chistian R, Guicciardi ME, Gores GJ. 2001. NF-κB is activated in cholestasis and functions to reduce liver injury. Am. J. Pathol. 158: 967-975.
91. 4 induced liver cirrhosis by silymarin. Fund. Clin. Pharmacol. 3: 183-191.
92. Muriel P. 2007a. Some experimental models of liver damage. In Hepatotoxicity: from Genomics to in Vitro and in Vivo Models, Sahu S (ed.). Wiley: Chichester; 119-137.
93. Muriel P. 2007b. Cytokines in liver diseases. In Hepatotoxicity: from Genomics to in Vitro and in Vivo Models, Sahu S (ed.). Wiley: Chichester; 371-389.
94. Muriel P, Escobar Y. 2003. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J. Appl. Toxicol. 23: 103-108.
95. Muriel P, Mourelle M. 1990a. Prevention by silymarin of membrane alterations in acute liver damage. J. Appl. Toxicol. 10: 275-279.
96. Muriel P, Mourelle M. 1990b. The role of membrane composition in ATPases activities of cirrhotic rats. Effect of silymarin. J. Appl. Toxicol. 10: 281-284.
97. Muriel P, Rivera-Espinoza Y. 2008. Beneficial drugs for liver diseases. J. Appl. Toxicol. 28: 93-103.
98. Muriel P, Suárez OR. 1994. Role of lipid peroxidation on biliary obstruction in the rat. J. Appl. Toxicol. 14: 423-426.
99. Muriel P, Alba N, Pérez-Álvarez VM, Shibayama M, Tsutsumi VK. 2001. Kupffer cells inhibition prevents hepatic lipid peroxidation and damage induced by carbon tetrachloride. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 130: 219-226.
100. 4-cirhosis in the rat. Eur. J. Hepatol. Gastroenterol. 15: 951-957.
101. Natarajan A, Wagner B, Sibilia M. 2007. The EGF receptor is required for efficient liver regeneration. Proc. Natl Acad. Sci. USA. 104: 17081-17086.
102. Natarajan K, Singh S, Burke TR, Grunberger D, Aggarwal BB. 1996. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-κB. Proc. Natl Acad. Sci. USA 93: 9090-9095.
103. Naugler WE, Karin M. 2008. NF-κB and cancer-identifying targets and mechanisms. Curr. Opin. Genet. Dev. 18: 19-26.
104. Oakley F, Mann J, Nailard S, Smart DE, Mungalsingh N, Costandinou C, Ali S, Wilson SJ, Millward-Sadler H, Iredale JP, Mann DA. 2005. Nuclear factor-κB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am. J. Pathol. 166: 695-708.
105. Ohishi T, Saito H, Tsusaka K, Inagaki H, Hamada Y, Kumagai N, Atsukawa K, Ishii H. 2001. Antifibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats. Hepatol. Res. 21: 147-158.
106. Parsons CJ, Takashima M, Rippe RA. 2007. Molecular mechanisms of hepatic fibrogenesis. J. Gastroenterol. Hepatol. 22: S79-S84.
107. Pascual C, González R, Armesto J, Muriel P. 1993. Effect of silymarin and silybinin on oxygen radicals. Drug Devl. Res. 29: 73-77.
108. Patel T, Bronk SF, Gores GL. 1994. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes. J. Clin. Invest. 94: 2183-2192.
109. Patel T, Roberts LR, Jones BA, Gores GL. 1998. Dysregulation of apoptosis as a mechanism of liver disease: an overview. Semin. Liver Dis. 18: 105-114.
110. Pendurthi UR, Williams JT, Rao LV. 1999. Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells: a possible mechanism for the cardiovascular benefits associated with moderate consumption of wine. Arterioscler. Thromb. Vasc. Biol. 19: 419-426.
111. Pérez-Álvarez V, Bobadilla RA, Muriel P. 2001. Structure-hepatoprotective activity relationship of 3,4-dihydroxycinnamic acid (caffeic acid) derivatives. J. Appl. Toxicol. 21: 527-531.
112. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. 2004. NF-kappaB functions as a tumor promoter in inflammation-associated cancer. Nature 431: 461-466.
113. Pinzani M, Marra F, Carloni V. 1998. Signal transduction in hepatic stellate cells. Liver 18: 2-13.
114. Pradhan SC, Girish C. 2006. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J. Med. Res. 124: 491-504.
115. Racanelli V, Rehermann B. 2006. The liver as an immunological organ. Hepatology 43: S54-S62.
116. 4 in the rat. Drug Dev. Res. 36: 125-128.
117. 4 in rats. Role of TGF-β modulation and oxidative stress. Fundam. Clin. Invest. 22: 417-427.
118. Reyes-Gordillo K, Segovia J, Shibayama M, Vergara P, Moreno MG, Muriel P. 2007. Curcumin protects against acute liver damage in the rat by inhibiting NF-κB, proinflammatory cytokines production and oxidative stress. Biochim. Biophys. Acta 1770: 989-996.
119. 4 in the rat. J. Appl. Toxicol. 28: 147-155.
120. Rust C, Karnitz LM, Paya CV, Moscat J. Simari RD, Gores GL. 2000. The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J. Biol. Chem. 275: 20210-20216.
121. Salazar-Montes A, Rincon AR, Panduro A, Armendariz-Borunda J. 1999. Chemically induced liver regeneration is characterized by specific IL-6 gene expression. Hepatol. Res. 15: 10-21.
122. Salazar-Montes A, Ruiz-Corro L, Sandoval-Rodriguez A, Lopez-Reyes A, Armendaris-Borunda J. 2006. Increased DNA binding activity of NF-κB, STAT-3, SMAD3 and AP-1 in acutely damaged liver. World J. Gastroenterol. 12: 5995-6001.
123. Saliou C, Rihn B, Cillard J, Okamoto T, Packer L. 1998. Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. FEBS Lett. 27: 8-12.
124. Santucci L, Fiorucci S, Chiorean M, Brunori PM, Di Matteo FM, Sidoni A, Migliorati G, Morelli A. 1996. Interleukin 10 reduces lethality and hepatic injury induced by lipopolysaccharide in galactosamine-sensitized mice. Gastroenterology 111: 736-744.
125. Schneider AW, Kalk FJ, Klein CP. 1999. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology 29: 334-339.
126. Schreck R, Meier B, Männel DN, Dröge W, Baeuerle PA. 1992. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175: 1181-1194.
127. Sener G, Toklu HZ, Sehirli O, Velioglu-Ogunc A, Cetinel S, Gedic N. 2006. Protective effects of resveratrol against acetaminophen-induced toxicity in mice. Hepatol. Res. 35: 62-68.
128. Sharma Y, Agarwal C, Singh AK, Agarwal R. 2001. Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol. Carcinogen. 30: 224-236.
129. Sherman M. 2005. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin. Liver Dis. 25: 143-154.
130. Shin HH, Lee HW, Choi HS. 2003. Induction of nitric oxide synthase (NOS) by soluble glucocorticoid induced tumor necrosis factor receptor (sGITR) is modulated by IFN-gamma in murine macrophage. Exp. Mol. Med. 35: 175-180.
131. Singh S, Aggarwal BB. 1995. Activation of transcription factor NF-κB is suppressed by curcumin (dyferulolylmethane). J. Biol. Chem. 270: 24995-2500.
132. Stancovski RS, Baltimore D. 1997. NF-kappaB activation: the I kappaB kinase revealed? Cell 91: 299-302.
133. Taub R, Greenbaum LE, Peng Y. 1999. Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration. Semin. Liver Dis. 19: 117-127.
134. Tergaonkar V, Correa RG, Ikawa M, Verna IM. 2005. Distinct roles of IkappaB proteins in regulating constitutive NF-kappaB activity. Nat. Cell. Biol. 7: 921-923.
135. Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H, Tejima K, Nagashima K, Nishikawa T, Fujiwara K. 2002. Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem. Biophys. Res. Commun. 297: 1108-1111.
136. Tsai SH, Lin-Shiau SY, Lin JK. 1999. Suppression of nitric oxide synthase and the down regulation of the activation of NF kappa B in macrophages by resveratrol. Br. J. Pharmacol. 126: 673-680.
137. Tuncer I, Ozbek H, Ugras S, Bayram I. 2003. Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat. The effect of AT1-R blocker on the hepatic fibrosis. Exp. Toxicol. Pathol. 55: 159-166.
138. Vainer GW, Pikarsky E, Ben-Neriah Y. 2008. Contradictory functions of NF-κB in liver physiology and cancer. Cancer Lett. 267: 182-188.
139. Vejchapipat P, Theamboonlers A, Chaokhonchai R, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. 2004. Serum hepatocyte growth factor and clinical outcome in biliary atresia. J. Pediatr. Surg. 39: 1045-1049.
140. Wadsworth TL, Koop DR. 1999. Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. Biochem. Pharmacol. 57: 941-949.
141. Wahl C, Bochtler P, Schirmbeck R, Reimann J. 2007. Type I FN-producing CD4 valpha 14i NKT cells facilitate priming of IL-10-producing CD8 T cells by hepatocytes. J. Immunol. 178: 2083-2093.
142. Walle T, Hsieh F, Delegge MH, Oatis JE Jr, Walle K. 2004. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dis. 32: 1377-1382.
143. Wang SC, Ohata M, Schrum L, Rippe RA, Tsukamoto H. 1998. Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. J. Biol. Chem. 273: 302-308.
144. Watabe M, Hishikawa K, Takayanagi A, Shimizu N, Nakaki T. 2004. Caffeic acid phenethyl ester induces apoptosis by inhibition of NFκB and activation of Fas in human breast cancer MCF-7 cells. J. Biol. Chem. 279: 6017-6026.
145. Weber LW, Boll M, Stampfl A. 2003. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit. Rev. Toxicol. 33: 105-136.
146. Weih F, Carrasco D, Durham SK, Barlon DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R. 1995. Multi-organ inflammation and hematopoietic abnormalities in mice with targeted disruption of RelB, a member of the NF-κB/Rel family. Cell 80: 331-340.
147. -/- double knockout mice. J. Exp. Med. 185: 1359-1370.
148. Wick MJ, Leithauser F, Reimann J. 2002. The hepatic immune system. Crit. Rev. Immunol. 22: 47-103.
149. Winn LM, Kim PM, Wells PG. 1998. Investigation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone for in vivo and in vitro muriene embriopathyand and embrionic ras mutations. J. Pharmacol. Exp. Ther. 287: 1128-1135.
150. Xia Y, Chen S, Wang Y, Mackman N, Ku G, Lo D, Feng L. 1999. RelB modulation of IκBα stability as a mechanism of transcription suppression of interleukin-1α (IL-1α), IL-1β and tumor necrosis factor alpha in fibroblast. Mol. Cell Biol. 19: 7688-7696.
151. Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM. 1998. Effect of chronic ethanol consumption on cytokine regulation of liver regeneration. Am. J. Physiol. 275: G696-G704.
152. Zi X, Zhang J, Agarwal R, Pollac M. 2000. Silibinin up-regulates insulin-like growth factor binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res. 60: 5617-5620.