© 1999 Oxford University Press
Article |
Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators
1 Laboratory of Hepatobiology and Toxicology, CB#7365, MEJB, Curriculum in Toxicology,
2 Department of Pharmacology and
3 Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7365 and
4 Chemical Industry Institute of Toxicology, Research Triangle Park, NC, USA
Increased cell proliferation most likely plays a key role in peroxisome proliferator-induced liver cancer. Recently, Kupffer cells were shown to be responsible for Wy-14,643-induced cell proliferation. However, the mechanism by which peroxisome proliferators activate Kupffer cells is unknown. Since gut-derived endotoxin is a known activator of Kupffer cells, the hypothesis that it is involved was evaluated. Increased cell proliferation and peroxisome induction were unaffected by gut sterilization. Moreover, endotoxin was not detectable in portal blood following treatment with Wy-14,643. Therefore, it is concluded that gut-derived endotoxin is not responsible for Kupffer cell activation. To test the hypothesis that Kupffer cells are activated by Wy-14,643 directly, Kupffer cell superoxide production was measured following treatment in vitro. Wy-14,643 increased superoxide production in a dose-dependent manner (0.1 and 50 µM) with half-maximal stimulation at 2.5 µM. Diethylhexylphthalate (DEHP) and ethylhexanol did not increase superoxide production even at doses 50 times higher than Wy-14,643; however, monoethylhexylphthalate (MEHP) activated superoxide production as effectively as Wy-14,643 with half-maximal stimulation at 5 µM. Treatment with Wy-14,643 for 21 days caused a 2-fold increase in Kupffer cell superoxide production while DEHP did not. Pretreatment of Kupffer cells with staurosporine (0.01–10 pM) completely blocked generation of superoxide demonstrating that protein kinase C is required. Moreover, Wy-14,643 increased Kupffer cell protein kinase C activity 3-fold. Pretreatment of Kupffer cells with the amino acid glycine (0.01–3 mM), which blunts calcium signaling, inhibited Wy-14,643-stimulated superoxide production and increased protein kinase C activity completely. These data are consistent with the hypothesis that potent peroxisome proliferators (Wy-14,643 and MEHP) directly activate Kupffer cell production of oxidants via mechanisms involving protein kinase C. Further, peroxisome proliferator treatments that sustain elevated rates of cell proliferation (e.g. Wy-14,643) activate Kupffer cell superoxide production following long-term dietary treatment supporting the hypothesis that Kupffer cell-derived oxidants are involved in peroxisome proliferator-induced neoplasia.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. B Ropero, P. Juan-Pico, A. Rafacho, E. Fuentes, F J. Bermudez-Silva, E. Roche, I. Quesada, F. R. de Fonseca, and A. Nadal Rapid non-genomic regulation of Ca2+ signals and insulin secretion by PPAR{alpha} ligands in mouse pancreatic islets of Langerhans J. Endocrinol., February 1, 2009; 200(2): 127 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 O. S. Gardner, B. J. Dewar, and L. M. Graves Activation of Mitogen-Activated Protein Kinases by Peroxisome Proliferator-Activated Receptor Ligands: An Example of Nongenomic Signaling Mol. Pharmacol., October 1, 2005; 68(4): 933 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Teissier, A. Nohara, G. Chinetti, R. Paumelle, B. Cariou, J.-C. Fruchart, R. P. Brandes, A. Shah, and B. Staels Peroxisome Proliferator-Activated Receptor {alpha} Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR-{alpha} Activation Properties Circ. Res., December 10, 2004; 95(12): 1174 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. S. Gardner, B. J. Dewar, H. S. Earp, J. M. Samet, and L. M. Graves Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., November 21, 2003; 278(47): 46261 - 46269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lawrence, C. M. Jones, P. Wardman, and M. J. Burkitt Evidence for the Role of a Peroxidase Compound I-type Intermediate in the Oxidation of Glutathione, NADH, Ascorbate, and Dichlorofluorescin by Cytochrome c/H2O2: IMPLICATIONS FOR OXIDATIVE STRESS DURING APOPTOSIS J. Biol. Chem., August 8, 2003; 278(32): 29410 - 29419. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Cosulich, N. James, and R. Roberts Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators Carcinogenesis, April 1, 2000; 21(4): 579 - 584. [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]
|
|
|
|
|
|
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]
|
|