Carcinogenesis, Vol 19, 1217-1222, Copyright © 1998 by Oxford University Press
I Rusyn, H Tsukamoto and RG Thurman
Stimulation of cell proliferation caused by peroxisome proliferators was
blocked by antibodies against TNF alpha and agents that inactivate Kupffer
cells, a rich source of TNF alpha, which supports the hypothesis that
Kupffer cells play a pivotal role in peroxisome proliferator-induced
hyperplasia. Here, the ability of the very potent peroxisome proliferator
WY-14 643 to activate the transcription factor NF-kappaB in rat liver was
examined since it is involved in TNF alpha production. Female
Sprague-Dawley rats were treated by gavage with WY- 14 643 (100 mg/kg)
while control animals were given equivalent doses of vehicle (olive oil).
Activation of NF-kappaB in both whole liver, non- parenchymal cells,
Kupffer cells and hepatocytes was assessed for up to 36 h using an
electrophoretic mobility shift assay. In whole liver, WY- 14 643
transiently increased NF-kappaB binding maximally 3.5-fold in 2- 8 h
followed by a steady decline to near control levels at 36 h. As early as 2
h after WY-14 643 treatment, the active form of NF-kappaB was localized
predominantly in Kupffer cells with values 20- to 25- times greater than in
hepatocytes. In hepatocytes, a small increase in NF-kappaB binding was
observed but only 8 h after WY-14 643 administration. Pre-treatment with
allopurinol, a xanthine oxidase inhibitor and free radical scavenger,
suppressed NF-kappaB activation by WY-14 643 almost completely. It is
concluded that NF-kappaB is activated by reactive oxygen species and plays
a central role in the mechanism of action of peroxisome proliferators.
Moreover, these findings support the hypothesis that Kupffer cells play a
pivotal role in peroxisome proliferator-induced hepatocyte proliferation
through rapid NF-kappaB activation and subsequent induction of TNF alpha
production. TNF alpha from Kupffer cells stimulates growth in parenchymal
cells later via mechanisms that also involve NF-kappaB.
ARTICLES
WY-14 643 rapidly activates nuclear factor kappaB in Kupffer cells before hepatocytes
Laboratory of Hepatobiology and Toxicology, University of North Carolina at Chapel Hill, 27599-7365, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. G. Woods, A. M. Burns, B. U. Bradford, P. K. Ross, O. Kosyk, J. A. Swenberg, M. L. Cunningham, and I. Rusyn WY-14,643 Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase Toxicol. Sci., August 1, 2007; 98(2): 366 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yang, S. Ito, and F. J. Gonzalez Hepatocyte-restricted constitutive activation of PPAR{alpha} induces hepatoproliferation but not hepatocarcinogenesis Carcinogenesis, June 1, 2007; 28(6): 1171 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Roberts, P. E. Ganey, C. Ju, L. M. Kamendulis, I. Rusyn, and J. E. Klaunig Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis Toxicol. Sci., March 1, 2007; 96(1): 2 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. F. Cariello, E. H. Romach, H. M. Colton, H. Ni, L. Yoon, J. G. Falls, W. Casey, D. Creech, S. P. Anderson, G. R. Benavides, et al. Gene Expression Profiling of the PPAR-alpha Agonist Ciprofibrate in the Cynomolgus Monkey Liver Toxicol. Sci., November 1, 2005; 88(1): 250 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Elrick, J. A. Kramer, C. L. Alden, E. A. G. Blomme, R. T. Bunch, M. A. Cabonce, S. W. Curtiss, L. D. Kier, K. L. Kolaja, C. P. Rodi, et al. Differential Display in Rat Livers Treated for 13 Weeks with Phenobarbital Implicates a Role for Metabolic and Oxidative Stress in Nongenotoxic Carcinogenicity Toxicol Pathol, January 1, 2005; 33(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Cattley Peroxisome Proliferators and Receptor-Mediated Hepatic Carcinogenesis Toxicol Pathol, February 1, 2004; 32(2_suppl): 6 - 11. [Abstract] [PDF]
|
|
|
|
 |
|
 M. D. Wheeler, O. M. Smutney, and R. J. Samulski Secretion of Extracellular Superoxide Dismutase From Muscle Transduced With Recombinant Adenovirus Inhibits the Growth of B16 Melanomas in Mice Mol. Cancer Res., October 1, 2003; 1(12): 871 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Kramer, E. A.G. Blomme, R. T. Bunch, J. C. Davila, C. J. Jackson, P. F. Jones, K. L. Kolaja, and S. W. Curtiss Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate Toxicol Pathol, June 1, 2003; 31(4): 417 - 431. [Abstract] [PDF]
|
|
|
|
 |
|
 M. D. Wheeler and R. G. Thurman Up-regulation of CD14 in Liver Caused by Acute Ethanol Involves Oxidant-dependent AP-1 Pathway J. Biol. Chem., February 28, 2003; 278(10): 8435 - 8441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Wheeler, O. M. Smutney, J. F. Check, I. Rusyn, R. Schulte-Hermann, and R. G. Thurman Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G302 - G312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Siesky, L. M. Kamendulis, and J. E. Klaunig Hepatic Effects of 2-Butoxyethanol in Rodents Toxicol. Sci., December 1, 2002; 70(2): 252 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. O'Brien, M. L. Cunningham, B. T. Spear, and H. P. Glauert Peroxisome Proliferators Do Not Activate the Transcription Factors AP-1, Early Growth Response-1, or Heat Shock Factors 1 and 2 in Rats or Hamsters Toxicol. Sci., September 1, 2002; 69(1): 139 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Fischer, H. P. Glauert, T. Yin, M. L. Sweeney-Reeves, N. Larmonier, and M. C. Black Moderate Iron Overload Enhances Lipid Peroxidation in Livers of Rats, but Does Not Affect NF-{kappa}B Activation Induced by the Peroxisome Proliferator, Wy-14,643 J. Nutr., September 1, 2002; 132(9): 2525 - 2531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hasmall, G. Orphanides, N. James, W. Pennie, K. Hedley, A. Soames, I. Kimber, and R. Roberts Downregulation of Lactoferrin by PPAR{alpha} Ligands: Role in Perturbation of Hepatocyte Proliferation and Apoptosis Toxicol. Sci., August 1, 2002; 68(2): 304 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakatani, N. Tsuboyama-Kasaoka, M. Takahashi, S. Miura, and O. Ezaki Mechanism for Peroxisome Proliferator-activated Receptor-alpha Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes J. Biol. Chem., March 8, 2002; 277(11): 9562 - 9569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Anderson, C. S. Dunn, R. C. Cattley, and J.C. Corton Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF{alpha} signaling Carcinogenesis, November 1, 2001; 22(11): 1843 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cui, H. Kawashima, T. B. Barclay, J. M. Peters, F. J. Gonzalez, E. T. Morgan, and H. W. Strobel Molecular Cloning and Regulation of Expression of Two Novel Mouse CYP4F Genes: Expression in Peroxisome Proliferator-Activated Receptor alpha -Deficient Mice upon Lipopolysaccharide and Clofibrate Challenges J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 542 - 550. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. D. Wheeler, S. Yamashina, M. Froh, I. Rusyn, and R. G. Thurman Adenoviral gene delivery can inactivate Kupffer cells: role of oxidants in NF-{kappa}B activation and cytokine production J. Leukoc. Biol., April 1, 2001; 69(4): 622 - 630. [Abstract] [Full Text]
|
|
|
|
 |
|
 I. Rusyn, M. B. Kadiiska, A. Dikalova, H. Kono, M. Yin, K. Tsuchiya, R. P. Mason, J. M. Peters, F. J. Gonzalez, B. H. Segal, et al. Phthalates Rapidly Increase Production of Reactive Oxygen Species in Vivo: Role of Kupffer Cells Mol. Pharmacol., April 1, 2001; 59(4): 744 - 750. [Abstract] [Full Text]
|
|
|
|
|
|
W. Parzefall, W. Berger, E. Kainzbauer, O. Teufelhofer, R. Schulte-Hermann, and R. G. Thurman Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes Carcinogenesis, March 1, 2001; 22(3): 519 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Elangbam, R. D. Tyler, and R. M. Lightfoot Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation--An Update Toxicol Pathol, February 1, 2001; 29(2): 224 - 231. [Abstract] [PDF]
|
|
|
|
|
|
I. Rusyn, M. F. Denissenko, V. A. Wong, B. E. Butterworth, M. L. Cunningham, P. B. Upton, R. G. Thurman, and J. A. Swenberg Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency Carcinogenesis, December 1, 2000; 21(12): 2141 - 2145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Hasmall, D. A. West, K. Olsen, and R. A. Roberts Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro Carcinogenesis, December 1, 2000; 21(12): 2159 - 2165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Cosulich, N. H. James, M. R.C. Needham, P. P. Newham, K. R. Bundell, and R. A. Roberts A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin Carcinogenesis, September 1, 2000; 21(9): 1757 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Rusyn, S. Yamashina, B. H. Segal, R. Schoonhoven, S. M. Holland, R. C. Cattley, J. A. Swenberg, and R. G. Thurman Oxidants from Nicotinamide Adenine Dinucleotide Phosphate Oxidase Are Involved in Triggering Cell Proliferation in the Liver Due to Peroxisome Proliferators Cancer Res., September 1, 2000; 60(17): 4798 - 4803. [Abstract] [Full Text]
|
|
|
|
|
|
H. Kono, I. Rusyn, B. U. Bradford, H. D. Connor, R. P. Mason, and R. G. Thurman Allopurinol Prevents Early Alcohol-Induced Liver Injury in Rats J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 296 - 303. [Abstract] [Full Text]
|
|
|
|
|
|
R. T. Miller, S. P. Anderson, J.C. Corton, and R. C. Cattley Apoptosis, mitosis and cyclophilin-40 expression in regressing peroxisome proliferator-induced adenomas Carcinogenesis, April 1, 2000; 21(4): 647 - 652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Peters, I. Rusyn, M. L. Rose, F. J. Gonzalez, and R. G. Thurman Peroxisome proliferator-activated receptor {alpha} is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis Carcinogenesis, April 1, 2000; 21(4): 823 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Rusyn, C. A. Bradham, L. Cohn, R. Schoonhoven, J. A. Swenberg, D. A. Brenner, and R. G. Thurman Corn oil rapidly activates nuclear factor-{kappa}B in hepatic Kupffer cells by oxidant-dependent mechanisms Carcinogenesis, November 1, 1999; 20(11): 2095 - 2100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Roberts and I. Kimber Cytokines in non-genotoxic hepatocarcinogenesis Carcinogenesis, August 1, 1999; 20(8): 1397 - 1402. [Full Text] [PDF]
|
|
|
|
|
|
B. Kroll, S. Kunz, T. Klein, and L. R. Schwarz Effect of lindane and phenobarbital on cyclooxygenase-2 expression and prostanoid synthesis by Kupffer cells Carcinogenesis, August 1, 1999; 20(8): 1411 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Hill, S. Clarke, K. Rodgers, B. Thornhill, J. M. Peters, F. J. Gonzalez, and J. M. Gimble Effect of Peroxisome Proliferator-Activated Receptor Alpha Activators on Tumor Necrosis Factor Expression in Mice during Endotoxemia Infect. Immun., July 1, 1999; 67(7): 3488 - 3493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Eagon, A. G. Teepe, M. S. Elm, S. D. Tadic, M. J. Epley, B. E. Beiler, H. Shinozuka, and K. N. Rao Hepatic hyperplasia and cancer in rats: alterations in copper metabolism Carcinogenesis, June 1, 1999; 20(6): 1091 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Chevalier, N Macdonald, and R. Roberts Induction of DNA replication by peroxisome proliferators is independent of both tumour necrosis factor (alpha) priming and EGF-receptor tyrosine kinase activity J. Cell Sci., January 12, 1999; 112(24): 4785 - 4791. [Abstract] [PDF]
|
|
|
|
|
|
M. L. Rose, C. A. Rivera, B. U. Bradford, L. M. Graves, R. C. Cattley, R. Schoonhoven, J. A. Swenberg, and R. G. Thurman Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators Carcinogenesis, January 1, 1999; 20(1): 27 - 33. [Abstract] [Full Text] [PDF]
|
|