The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis
Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFβ), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-κ B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
Keywordsapoptosis hepatic stellate cells liver fibrosis NF-kB
Jaeschke H. Cellular adhesion molecules: Regulation and functional significance in the pathogenesis of liver diseases. Am J Physiol Gastroinest Liver Physiol
; G602–G611.Google Scholar
Pinzani M, Marra F. Cytokine receptors and signalling in hepatic stellate cells. Semin Liver Dis
: 397–426.CrossRefPubMedGoogle Scholar
Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem
: 2247–2250.CrossRefPubMedGoogle Scholar
Fallowfield JA, Iredale JP. Reversal of liver fibrosis and cirrhosis–an emerging reality. Scott Med J
: 3–6.PubMedGoogle Scholar
Pinzani M, Rombouts K. Liver fibrosis: From the bench to clinical targets. Dig Liver Dis
: 231–242.CrossRefPubMedGoogle Scholar
Knittel T, Kobold D, Saile B, et al.
Rat liver myofibroblasts and hepatic stellate cells: Different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology
: 1205–1221.PubMedGoogle Scholar
Forbes SJ, Russo FP, Rey V, et al.
A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology
: 955–963.CrossRefPubMedGoogle Scholar
Iredale JP. Cirrhosis: New research provides a basis for rational and targeted treatment. BMJ
: 143–147.CrossRefPubMedGoogle Scholar
Friedman SL. The cellular basis of hepatic fibrosis: Mechanisms and treatment strategies. N Engl J Med
: 1823–1835.Google Scholar
Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: The principle collagen producing cells of normal rat liver. Proc Natl Acad Sci USA
: 8681–8685.PubMedGoogle Scholar
Maher JJ. Interactions between hepatic stellate cells and the immune system. Semin Liver Dis
: 417–426.CrossRefPubMedGoogle Scholar
Iredale JP, Benyon RC, Arthur MJP, et al.
Tissue inhibitor of metalloproteinase-1 messenger RNA in experimental liver injury and fibrosis. Hepatology
: 176–184.PubMedGoogle Scholar
Arthur MJP, Iredale JP, Mann DA. Tissue inhibitors of metalloproteinases: Role in liver fibrosis and alcoholic liver disease. Alcohol Clin Exp Res
: 940–943.PubMedGoogle Scholar
Bonis PAL, Freidman SL, Kaplan MM. Is liver fibrosis reversible. N Engl J Med
: 452–454.CrossRefPubMedGoogle Scholar
Arthur MJP. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology
: 1525–1528.CrossRefPubMedGoogle Scholar
Poynard T, McHutchinson J, Manns M, et al.
Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology
: 1303–1313.CrossRefPubMedGoogle Scholar
Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med
: 981–985.PubMedGoogle Scholar
Wanless IR. Use of corticosteroid therapy in autoimmune hepatitis resulting in resolution of cirrhosis. J Clin Gastroenterol
: 371–372.CrossRefPubMedGoogle Scholar
Kaplan MM, DeLillis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med
: 682–688.PubMedGoogle Scholar
Kweon YO, Goodman ZD, Dienstag JL, et al.
Decreasing fibrogenesis: An immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol
: 749–755.CrossRefPubMedGoogle Scholar
Hammel P, Coulevard A, O’Toole D, et al.
Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med
: 418–423.CrossRefPubMedGoogle Scholar
Fogo AB. Mesangial matrix modulation and glomerulosclerosis. Exp Nephrol
: 147–159.CrossRefPubMedGoogle Scholar
Yang F, Yang XP, Liu YH, et al.
Ac-SKDP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction. Hypertension
: 229–236.CrossRefPubMedGoogle Scholar
Iredale JP, Benyon RC, Pickering J, et al.
Mechanisms of spontaneous resolution of rat liver fibrosis—hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest
: 538–549.PubMedGoogle Scholar
Issa R, Williams E, Trim N, et al.
Apoptosis of hepatic stellate cells: Involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut
: 548– 557.CrossRefPubMedGoogle Scholar
Salvesen GS, Abrams JM. Caspase activation—stepping on the gas or releasing the brakes? Oncogene
: 2774–2784.CrossRefPubMedGoogle Scholar
Norbury CJ and Zhivotovsky B. DNA damage-induced apoptosis. Oncogene
: 2797–2808.CrossRefPubMedGoogle Scholar
Canbay A, Friedman S, Gores GJ. Apoptosis: The nexus of liver injury and fibrosis. Hepatology
: 273–278.CrossRefPubMedGoogle Scholar
Lee JI, Lee KS, Paik YH, et al.
Apoptosis of hepatic stellate cells in carbon tetrachloride induced acute liver injury of the rat: Analysis of isolated hepatic stellate cells. J Hepatol
: 960–966.CrossRefPubMedGoogle Scholar
Wright MC, Issa R, Smart DE, et al.
Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances resolution of fibrosis in rats. Gastroenterology
: 685–698.CrossRefPubMedGoogle Scholar
Jaatela M. Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene
: 2746–2756.PubMedGoogle Scholar
Trim N, Issa R, Krane S, Benyon RC, Iredale JP. Intact collagen-1 inhibits hepatic stellate cell activation and promotes persistence of activated HSC in vivo
: 183A.Google Scholar
Issa R, Zhou X, Trim N, et al.
Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4
-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J
: 47–49.PubMedGoogle Scholar
Issa R, Zhou X, Constandinou CM, et al.
Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology
: 1795–1808.CrossRefPubMedGoogle Scholar
Zhou X, Murphy FR, Gedhu N, Zhang J, Iredale JP, Benyon RC. Engagement of αv
integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem
: 23996–24006.CrossRefPubMedGoogle Scholar
Iwamoto H, Sakai H, Tada S, Nakamuta M, Nawata H. Induction of apoptosis in rat hepatic stellate cells by disruption of integrin-mediated cell adhesion. J Lab Clin Med
: 83–89.CrossRefPubMedGoogle Scholar
Murphy FR, Issa R, Zhou X, et al.
Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects in matrix metalloproteinase inhibition. J Biol Chem
: 11069–11076.CrossRefPubMedGoogle Scholar
Yoshiji H, Kuriyama S, Yoshii J, et al.
Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology
: 850–860.PubMedGoogle Scholar
Preaux AM, D’ortho MP, Bralet MP, Laperche Y, Mavier P. Apoptosis of human human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2. Hepatology
: 615–622.CrossRefPubMedGoogle Scholar
Liu XW, Bernardo MM, Fridman R, Kim HR. Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. J Biol Chem
: 40364–40372.CrossRefPubMedGoogle Scholar
Murphy F, Wuang J, Collins J, et al.
N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. Comp Hepatol
: S8.CrossRefGoogle Scholar
Liu XJ, Yang L, Wu H-B, Qiang O, Huang MH, Wang YP. Apoptosis of rat hepatic stellate cells induced by anti-focal adhesion kinase antibody. World J Gastroenterol
: 734–738.PubMedGoogle Scholar
Fischer R, Cariers A, Reinehr R, Haussinger D. Caspase 9 dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology
: 845–861.CrossRefPubMedGoogle Scholar
Canbay A, Feldstein AE, Higuchi H, et al.
Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology
: 1188–1198.CrossRefPubMedGoogle Scholar
Duffield JS, Forbes SJ, Constandinou CM, et al.
Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest
: 56–65.CrossRefPubMedGoogle Scholar
Trim N, Morgan S, Evans M, et al.
Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol
: 1235–1243.PubMedGoogle Scholar
Oakley F, Trim N, Constandinou CM, et al.
Hepatocytes express nerve growth factor during liver injury. Am J Pathol
: 1849–1858.PubMedGoogle Scholar
Saile B, DeRocco P, Dudas J, et al.
IGF-I induces DNA synthesis and apoptosis in rat liver hepatic stellate cells (HSC) but DNA synthesis and proliferation in rat liver myofibroblasts (rMF). Lab Invest
: 1037–1049.CrossRefPubMedGoogle Scholar
Saile B, Matthes N, Knittel T, Ramadori G. Transforming growth factor beta and tumour necrosis factor alpha inhibit both apoptosis and proliferation of activated hepatic stellate cells. Hepatology
: 196–202.CrossRefPubMedGoogle Scholar
Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G. The blc, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta and TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol
: 554–561.CrossRefPubMedGoogle Scholar
Varela-Ray M, Montiel-Duarte C, Oses-Prieto JA, et al.
p38 MAPK mediates the regulation of α 1(I) procollagen mRNA levels by TNF-α and TGF-β in a cell line of rat hepatic stellate cells. FEBS Letters
: 133–138.CrossRefPubMedGoogle Scholar
Saile B, Knittel T, Matthes N, Schott P, Ramadori G. CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during tissue repair. Am J Pathol
: 1265–1272.PubMedGoogle Scholar
Gong W, Pecci A, Roth S, Lahme B, Beato M, Gressner AM. Tranformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. Hepatology
: 492–502.CrossRefPubMedGoogle Scholar
Saile B, Matthes N, Neubauer K, et al.
Rat liver myofibroblasts and hepatic stellate cells differ in CD95-mediated apoptosis and response to TNF-α. Am J Physiol Gastrointest Liver Phsiol
: G435–G444.Google Scholar
Cariers A, Reinehr R, Fischer R, Warskulat U, Haussinger D. c-Jun-N-terminal kinase dependent membrane targeting of CD95 in rat hepatic stellate cells. Cell Physiol Biochem 2002; 12
: 179–186.CrossRefPubMedGoogle Scholar
Debatin KM, Krammer PH. Death receptors in chemotherapy and cancer. Oncogene
: 2950–2966.CrossRefPubMedGoogle Scholar
Wang XZ, Zhang SJ, Chen YX, Chen ZX, Huang YH, Zhang LJ. Effects of platelet-derived growth factor and interleukin-10 on Fas/Fas-ligand and Bcl-2/Bax mRNA expression in rat hepatic stellate cells in vitro
. World J Gastroenterol
: 2706–2710.PubMedGoogle Scholar
Thompson K, Maltby J, Fallowfield J, McAulay M, Millwall-Sadler H, Sheron N. Interleukin-10 expression and function in experimental murine inflammation and fibrosis. Hepatology
: 1597–1606.CrossRefPubMedGoogle Scholar
Galle PR, Hofmann WJ, Walczak H, et al.
Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med
: 1223–1230.CrossRefPubMedGoogle Scholar
Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al.
Lethal effect of the anti-Fas antibody in mice. Nature
: 806–809.CrossRefPubMedGoogle Scholar
Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ. Fas enhances fibrogenesis in the bile duct ligated mouse: A link between apoptosis and fibrosis. Gastroenterology
: 1323–1330.CrossRefPubMedGoogle Scholar
Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL mediated apoptosis. Hepatology
: 87–95.CrossRefPubMedGoogle Scholar
Saile B, Eisenbach C, El-Armouche H, Neubauer K, Ramadori G. Anti-apoptotic effect of interferon-alpha on hepatic stellate cells (HSC): A novel pathway of IFN-alpha signal transduction via Janus kinase 2 (JAK2) and caspase 8. Eur J Cell Biol
: 31–41.CrossRefPubMedGoogle Scholar
Saile B, Eisenbach C, Hammoudeh E, Ramadori G. Interferon-γgcts proapoptotic on hepatic stellate cell (HSC) and abrogates the antiapoptotic effect of interferon-α by an HSP70-dependant pathway. Eur J Cell Biol
: 469–476.CrossRefPubMedGoogle Scholar
Reynaert H, Rombouts K, Vandermonde A, et al.
Expression of somatostatin receptors in normal and cirrhotic human liver and in hepatocellular carcinoma. Gut
: 1180–1189.CrossRefPubMedGoogle Scholar
Pan Q, Li DG, Lu HM, Lu IY, Wang YQ, Xu QF. Antiproliferative and proapoptotic effects of somatostatin on activated hepatic stellate cells. World J Gastroenterol
: 1015–1018.PubMedGoogle Scholar
Oben JA, Roskams T, Yang S, et al.
Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut
: 438–445.CrossRefPubMedGoogle Scholar
Fischer R, Schmitt M, Bode JG, Haussinger D. Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells. Gastroenterology
: 1212–1226.CrossRefPubMedGoogle Scholar
Saxena NK, Titus MA, Ding X, et al.
Leptin is a novel profibrogenic cytokine in hepatic stellate cells: Mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (erk) and Akt phosphorylation. FASEB J
: 1612–1614.PubMedGoogle Scholar
Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. Leptin in hepatic fibrosis: Evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology
: 762–771.CrossRefPubMedGoogle Scholar
Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab
: 121–138.PubMedGoogle Scholar
Zamara E, Novo E, Marra F, et al.
4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol
: 60–68.CrossRefPubMedGoogle Scholar
Davaille J, Li L, Mallat A, Lotersztajn S. Sphingosine 1-phosphate triggers both apoptotic and survival for human hepatic myofibroblasts. J Biol Chem
: 37323–37330.Google Scholar
Zu J, Fu Y, Chen A. Activation of peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol Gastrointest Liver Physiol
: G20–G30.PubMedGoogle Scholar
Galli A, Crabb D, Price D, et al.
Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology
: 101–108.CrossRefPubMedGoogle Scholar
Zheng S, Chen A. Activation of PPAR-γ is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cell in vitro
. Biochem J
: 149–57.CrossRefPubMedGoogle Scholar
Montiel-Duarte C, Ansorena E, Lopez-Zabalza MJ, Cenarruzabeitia E, Iraburu MJ. Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine (“Ecstasy”) on hepatic stellate cells. Biochem Pharmacol
: 1025–1033.CrossRefPubMedGoogle Scholar
Thirunavukkarasu C, Watkins S, Harvey R, Gandhi C. Superoxide-induced apoptosis of activated rat hepatic stellate cells. J Hepatol
: 567–575.CrossRefPubMedGoogle Scholar
Zhu J, Wu J, Frizell E, et al.
Rapamycin inhibits hepatic stellate cell proliferation in vitro
and limits fibrogenesis in an in vivo
model of liver fibrosis. Gastroenterology
: 1198–1204.PubMedGoogle Scholar
Zhao YZ Kim JY, Park EJ, et al.
Tetrandrine induces apoptosis in hepatic stellate cells. Phytother Res
: 306–309.CrossRefPubMedGoogle Scholar
Kim JY, Kim KM, Nan JX, et al.
Induction of apoptosis by tanshinone I via cytochrome c release in activated hepatic stellate cells. Pharmacol Toxicol
: 195–200.CrossRefPubMedGoogle Scholar
Zhang XL, Liu L, Jiang HQ. Salvia miltiorrhiza monomer IH764-3 induces hepatic stellate cell apoptosis via caspase-3 activation. World J Gastroenterol
: 515–519.PubMedGoogle Scholar
Yao XX, Tang YW, Yao DM, Xiu HM. Effects of Yigan Decoction on proliferation and apoptosis of hepatic stellate cells. World J Gastroenterol
: 511–514.PubMedGoogle Scholar
Zhao WX, Zhao J, Liang CL, Zhao B, Pang RQ, Pan XH. Effect of caffeic acid phenethyl ester on proliferation and apoptosis of hepatic stellate cells in vitro
. World J Gastroenterol
: 1278–1281.PubMedGoogle Scholar
Dekel R, Zvibel I, Brill S, Brazovsky E, Halpern Z, Oren R. Gliotoxin ameliorates development of fibrosis and cirrhosis in a thioacetamide rat model. Dig Dis Sci
: 1642–1647.CrossRefPubMedGoogle Scholar
Orr JG, Leel V, Cameron GA, et al.
Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells. Hepatology
: 232–242.CrossRefPubMedGoogle Scholar
Kweon YO, Paik YH, Schnabl B, Qian T, Lemasters JJ, Brenner DA. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol
: 38–46.CrossRefPubMedGoogle Scholar
Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther
: 1191–1196.CrossRefPubMedGoogle Scholar
Canbay A, Guicciardi ME, Higuchi H, et al.
Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest
: 152–159.CrossRefPubMedGoogle Scholar
Abriss B, Hollweg G, Gressner AM, Weiskirchen R. Adenoviral mediated transfer of p53 or retinoblastoma protein blocks cell proliferation and induces apoptosis in culture-activated hepatic stellate cells. J Hepatol
: 169–178.CrossRefPubMedGoogle Scholar
Janeschek N, van de Leur E, Gressner AM, Weiskirchen R. Induction of cell death in activated hepatic stellate cells by targeted gene expression of the thymidine kinase/ganciclovir system. Biochem Biophys Res Commun
: 1107–1115.CrossRefPubMedGoogle Scholar
Pahl HL. Activators and target genes of Rel/NF-ΚB transcription factors. Oncogene
: 6853–6866.CrossRefPubMedGoogle Scholar
Baldwin AS. The transcription factor NF-ΚB and human disease. J Clin Invest
: 3–6.PubMedGoogle Scholar
Ghosh S, May MJ, Kopp EB. NF-ΚB and rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol
: 225–260.PubMedGoogle Scholar
Elsharkawy AM, Wright MC, Hay RT, et al.
Persistent activation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel rel-like factors and prolonged changes in the expression of IkappaB family proteins. Hepatology
: 761–769.CrossRefPubMedGoogle Scholar
Hellebrand C, Jobin C, Licato LL, Sartor RB, Brenner DA. Inhibition of NF-kappaB in activated rat hepatic stellate cells by proteosome inhibitors and an IkappaB super-repressor. Hepatology
: 1285–1295.CrossRefPubMedGoogle Scholar
Baeuerle PA, Baltimore D. NFkappaB: Ten years after. Cell
: 13–20.CrossRefPubMedGoogle Scholar
Hetts SW. To die or not to die; an overview of apoptosis and its role in disease. JAMA
: 300–307.CrossRefPubMedGoogle Scholar
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS. NF-ΚB anti-apoptosis: Induction of TRAF-1, TRAF-2, c-IAP1 and c-IAP2 to suppress caspase 8 activation. Science
: 1680–1683.Google Scholar
Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol
: 221–227.CrossRefGoogle Scholar
Lang A, Schoonhoven R Tuvia S, Brenner DA, Rippe RA. Nuclear factor kappaB in proliferation, activation and apoptosis in rat hepatic stellate cells. J Hepatol
: 49–58.CrossRefPubMedGoogle Scholar
Oakley F, Meso M, Iredale JP, et al.
Inhibition of IΚB kinases stimulates hepatic stellate cell apoptosis and accelerates recovery from liver fibrosis. Gastroenterology
: 108–120.CrossRefPubMedGoogle Scholar
Wahl C, Liptay S, Adler G, Schmit RM. Sulfasalazine: A potent and specific inhibitor of nuclear factor kappa B. J Clin Invest
: 1163–1174.PubMedGoogle Scholar
Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem
: 3863–3869.CrossRefPubMedGoogle Scholar
Papa S, Zazzeroni F, Bubici C, et al.
Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol
: 146–153.CrossRefPubMedGoogle Scholar
Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 2004; 23
: 2838–2849.PubMedGoogle Scholar
Bahr MJ, Vincent KJ, Arthur MJP, et al.
Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: Regulation by activator protein-1 DNA binding proteins. Hepatology
: 839–848.CrossRefPubMedGoogle Scholar
Czaja MJ. JNK/AP-1 regulation of hepatocyte death. Am J Physiol Gastroinest Liver Physiol
: G875–G879.Google Scholar
Uyama N, Shimahara Y, Okuyama H, et al.
Carbenoxlone inhibits DNA synthesis and collagen gene expression in rat hepatic stellate cells in culture. J Hepatol
: 749–755.CrossRefPubMedGoogle Scholar
Ikeda H, Nagahima K, Yanase M, et al.
Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells. Am J Physiol Gastroinest Liver Physiol
: G880–G886.Google Scholar
Saelens X, Festjens N, Vande Malle L, van Gurp M, van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene
: 2861–2874.CrossRefPubMedGoogle Scholar
Kawada N, Kristensen DB, Asahina K, et al.
Characterisation of a stellate cell activation-associated (STAP) with peroxidase activity found in rat hepatic stellate cells. J Biol Chem
: 25318–25323.CrossRefPubMedGoogle Scholar
Liu XJ, Yang L, Luo FM, Wu HB, Qiang Q. Association of differentially expressed genes with activation of mouse hepatic stellate cells by high density cDNA microarray. World J Gastroenterol
: 1600–1607.PubMedGoogle Scholar
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