Carcinogenesis

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Carcinogenesis, Vol. 21, No. 4, 823-826, April 2000
© 2000 Oxford University Press

Short Communications

Peroxisome proliferator-activated receptor is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis

Jeffrey M. Peters^2,*, Ivan Rusyn^1,*, Michelle L. Rose¹, Frank J. Gonzalez and Ronald G. Thurman¹

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 and
¹ Curriculum in Toxicology and Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA

	Abstract

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Peroxisome proliferators increase hepatocyte proliferation and cause liver tumors in rodents, yet the mechanism of action is not understood. Based on studies with null mice it is known that peroxisome proliferator-activated receptor- (PPAR) is involved. There is also evidence that Kupffer cells play a central role in peroxisome proliferator-induced carcinogenesis, most likely via mechanisms involving increases in superoxide, activation of nuclear factor B and production of tumor necrosis factor- (TNF). However, it is not known whether PPAR is constitutively expressed in Kupffer cells. Therefore, the expression of PPAR isoforms in rat Kupffer and parenchymal cells was examined. Kupffer cells and hepatocytes of >99% purity were isolated from rats fed either a control diet or one containing 0.1% WY-14,643 for 1 week. Protein and RNA were obtained and PPAR expression was analyzed using northern and western blots. PPAR, PPARß and PPAR mRNA was detected in purified hepatocytes. In Kupffer cells, mRNA encoding PPAR was present while transcripts for PPAR and PPARß were not detected. Immunoblots were consistent with the results found by northern analysis. Moreover, when Kupffer cells from wild-type or PPAR-null mice were treated with WY-14,643 in vitro, superoxide production was similar. Combined, these results show that PPAR is expressed in rat parenchymal cells but not in Kupffer cells. These data are consistent with the hypothesis that parenchymal cells respond to Kupffer cell-derived TNF via mechanisms dependent on PPAR within the parenchymal cells.

Abbreviations: DEHP, di(2-ethylhexyl)phthalate; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; HBSS, Hank's balanced salt solution; NF-B, nuclear factor B; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; PPAR, peroxisome proliferator-activated receptor; TNF, tumor necrosis factor-.

	Introduction

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Peroxisome proliferators are a diverse class of structurally unrelated compounds that cause marked increases in cell proliferation, elevate activity of enzymes associated with peroxisomal, microsomal and mitochondrial fatty acid oxidation and ultimately result in liver tumors in rodents (1,2). The mechanisms underlying the carcinogenic effect of these compounds are not known but susceptibility to these agents requires peroxisome proliferator-activated receptor (PPAR)-, since PPAR-null mice do not exhibit increased cell proliferation or develop liver tumors after feeding a potent peroxisome proliferator for up to 11 months (3). A number of non-exclusive hypotheses have been postulated to contribute to the mechanisms underlying this effect including: (i) oxidative damage to DNA or proteins resulting from increased intracellular levels of H₂O₂ (4); (ii) alterations in cell proliferation and cell cycle control (5,6); (iii) inhibition of apoptosis (7,8); (iv) a combination of these events.

The role of oxidative damage in peroxisome proliferator-induced carcinogenesis has been contested, in part due to a lack of correlation between peroxisome proliferation and tumorigenicity of di(2-ethylhexyl)phthalate (DEHP), a relatively weak peroxisome proliferator, versus WY-14,643, a relatively potent peroxisome proliferator (5). In contrast, a good correlation between increased replicative DNA synthesis associated with hyperplasia and the carcinogenicity of peroxisome proliferators has been reported (5), however, signaling events involved in stimulation of the cell cycle and its contribution to tumor formation remain unclear. Alternatively, since peroxisome proliferators inhibit apoptosis both in vivo (9) and in vitro (7,8), it is possible that inhibition of programmed cell death may predispose cells to ultimately form tumors, especially given the increase in signals for cell replication (10).

It has been proposed that Kupffer cells are causally responsible for the mitogenic effects of peroxisome proliferators (11). Specifically, the increase in tumor necrosis factor- (TNF) mRNA due to the peroxisome proliferator WY-14,643 is blocked by methyl palmitate and glycine, agents that inactivate Kupffer cells (12,13). Moreover, an increase in cell proliferation in liver due to WY-14,643 is blocked by antibodies to TNF (14). In addition, WY-14,643 activates the transcription factor nuclear factor B (NF-B), which is pivotal in TNF production, rapidly and nearly exclusively in the Kupffer cell fraction (15). Finally, WY-14,643 directly activates superoxide production and protein kinase C in isolated Kupffer cells (16). Taken together, there is considerable evidence in support of the hypothesis that peroxisome proliferators activate Kupffer cells to produce mitogenic levels of TNF via mechanisms dependent on oxidants and NF-B. On the other hand, experiments with null mice unequivocally demonstrate that hepatocellular proliferation and tumors due to peroxisome proliferators require PPAR (3). It is not clear how these possibilities can co-exist.

Therefore, it is first necessary to understand the cellular distribution of PPARs in liver. Accordingly, the expression of the three PPAR isoforms was examined in hepatocytes and Kupffer cells isolated from rats fed either a control diet (NIH-07) or one containing WY-14,643 [0.1% w/w 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid; Chemsyn Science Laboratories, Lenexa, KS] for 1 week. At the end of the experiment, hepatocytes and Kupffer cells were isolated from liver according to the method of Smedsrod and Pertoft (17). As shown in Figure 1, the purity of each cell preparation (top panel) was >99% as verified by uptake of fluorescein isothiocyanate (FITC)-labeled latex beads (Kupffer cells, middle panel) (18) and the presence of cytosolic ß-glucosidase (hepatocytes, bottom panel) using a fluorescent substrate, resorufin-ß-D-glucopyranoside (19). After the purity of each preparation was established, proteins and total cellular RNA were extracted from freshly prepared cells and used for western or northern blotting, respectively. Northern analysis of mRNA from hepatocytes showed that PPAR and PPAR were present at high levels and a weaker signal was found for PPARß (Figure 2). In contrast, mRNA for PPAR and PPARß were undetectable in Kupffer cells, while a signal of similar intensity to that observed in hepatocytes was found for PPAR (Figure 2). Western analysis of protein isolated from hepatocytes was consistent with the results obtained from RNA analysis. In hepatocytes, PPAR and PPAR were both detected (Figure 3). In Kupffer cells, PPAR was not detected in the immunoblots, but PPAR was present (Figure 3). The signal for PPAR was very high compared with the relative mRNA expression observed in the Kupffer cell samples. While WY-14,643 treatment resulted in an ~2-fold increase in PPAR mRNA in hepatocytes it did not increase signals for either mRNA or protein for PPAR in Kupffer cells. Western analysis using two different commercial antibodies against PPARß were inconclusive (data not shown) since they reacted with negative controls (samples obtained from PPARß-null mice).

View larger version (95K): [in this window] [in a new window]   Fig. 1. Determination of purity of hepatocytes and Kupffer cells. Cells were isolated from female Sprague–Dawley rat (weighing ~250 g; Charles River Breeding Laboratories) liver as described elsewhere (17) and 106 Kupffer cells (left) or hepatocytes (right) were plated in 60 cm Petri dishes on coverslips in Dulbecco's modified Eagle's medium supplemented with 5% fetal calf serum and antibiotics. First, resorufin-ß-D-glucopyranoside (final concentration 0.1 mM) was added for 30 min at 37°C and washed twice with phosphate-buffered saline (PBS). Second, 1 µm FITC-labeled latex beads (Polysciences, Warrington, PA) were added and cells were incubated for 5 min at 37°C, washed three times with PBS and fluorescence was determined in situ with a Universal Imaging Corp. Image-1/AT image acquisition and analysis system (Chester, PA) incorporating an Axioskop 50 microscope (Carl Zeiss, Thornwood, NY). The same microscopic field was photographed in normal light (upper) or with FITC (middle) or resorufin (bottom) filters. Representative experiment.

 

View larger version (75K): [in this window] [in a new window]   Fig. 2. Cellular distribution of RNA encoding PPAR isoforms in rat liver hepatocytes and Kupffer cells. Hepatocytes (Hep) and Kupffer (Kup) cells were isolated as described above from livers of female Sprague–Dawley rats (weighing ~250 g; Charles River Breeding Laboratories) fed control diet (NIH-07) (C) or one containing WY-14,643 (0.1% w/w) (WY) for 1 week. Total RNA was isolated using TRIZOL reagent (Gibco BRL, Grand Island, NY) using the manufacturer's instructions. Northern analysis of PPAR, PPARß, PPAR and ß-actin mRNA was performed using mouse cDNA probes as described previously (22). Representative data of four separate experiments.

 

View larger version (76K): [in this window] [in a new window]   Fig. 3. Immunoblots of hepatocyte and Kupffer cell protein. Hepatocytes or Kupffer cells from control (CON) or WY-14,643-treated (WY) female Sprague–Dawley rats (weighing ~250 g; Charles River Breeding Laboratories) were homogenized in lysis buffer (25 mM HEPES, 10 mM dithiothreitol, 15 mM MgCl2, 10 mM EDTA, 10 mM ß-glycerol phosphate, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin and 10 µg/ml aprotinin) and 30 µg of protein was electrophoresed on a 7.5% SDS–PAGE gel, followed by transfer to a nitrocellulose membrane. A monoclonal antibody against PPAR (kindly provided by Dr Gary Perdew, Pennsylvania State University) and a polyclonal antibody against PPAR (Affinity BioReagents, Golden, CO) were used for detection of PPAR isoforms, followed by anti-mouse or anti-rabbit secondary horseradish peroxidase-conjugated antibodies. Immunoreactive proteins were detected using ECL (Amersham Life Science, Arlington Heights, IL). Representative data.

 
The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are unknown but are clearly mediated by PPAR, since null mice neither respond with an increase in hepatocyte proliferation nor develop tumors after prolonged feeding with a potent peroxisome proliferator (3). PPAR has been detected in isolated hepatocytes (20). In this study, expression of the PPARs was examined in hepatocytes and Kupffer cells to determine if PPAR is involved in modulating gene expression in Kupffer cells, which have been causally linked to proliferator-induced hepatocarcinogenesis (11). PPAR and PPAR were detected at both the protein and mRNA levels in isolated hepatocytes. In contrast, PPAR mRNA and protein were not detected in Kupffer cells while PPAR was detected at substantial levels. These observations indicate that while Kupffer cells have a significant role in the mitogenic response accompanying peroxisome proliferation, PPAR is not involved in regulating gene expression in Kupffer cells. However, since PPAR-mediated changes in gene expression are required for the carcinogenic effects of peroxisome proliferators, it is concluded that these effects involve parenchymal cells based on the expression patterns of PPARs described in this work.

It was recently demonstrated that low levels of oxidants play an important role in signaling increases in cell proliferation caused by peroxisome proliferators via a Kupffer cell-mediated mechanism involving NFB and TNF (11). Kupffer cells are also capable of producing increased levels of superoxide after treatment with peroxisome proliferators as seen with in vitro cultures in this study and others (16). To determine if PPAR is involved in activation of Kupffer cells by peroxisome proliferators or not, pure Kupffer cells were isolated from wild-type and PPAR-null mice and superoxide production was measured (16). Basal rates of superoxide production were not different in Kupffer cells from wild-type and PPAR-null mice (Figure 4). Additionally, stimulation of superoxide production by either phorbol 12-myristate 13-acetate (PMA) or WY-14,643 resulted in similar increases in Kupffer cells from either wild-type or PPAR-null mice (Figure 4). This demonstrates that activation of Kupffer cells by peroxisome proliferators is not dependent on Kupffer cell PPAR. These data support the hypothesis that PPAR is not involved in activation of Kupffer cells by peroxisome proliferators.

View larger version (26K): [in this window] [in a new window]   Fig. 4. Superoxide production by Kupffer cells from wild-type and PPAR-null mice. Kupffer cells were isolated as described above from either wild-type or PPAR-null mice (female, Sv/129, 10 weeks old) and seeded at a density of 106 cells/ml in RPMI 1640 containing 10% fetal bovine serum (FBS) and penicillin/streptomycin (100 IU/ml and 100 µg/ml, respectively) in 24-well plates. One hour later, medium was replaced with fresh RPMI 1640 containing 30% FBS and cells cultured overnight. To measure superoxide, the medium was aspirated and Kupffer cells were washed twice with Hank's balanced salt solution (HBSS). Kupffer cells were incubated in HBSS with either 1 µM PMA (Sigma, St Louis, MO), 10 µM WY-14,643 (WY) or vehicle control (CON) (ethanol, 0.1% final concentration) and cultured for 30 min at 37°C. Superoxide was determined as a reduction in cytochrome c inhibitable by superoxide dismutase as described elsewhere (23). Data are presented as means ± SEM. Asterisks (*) denote statistical differences from control (P < 0.05, two-way ANOVA with Bonferroni post-hoc tests) in the PMA and WY-14,643 groups (n = 4 in each group).

 
Peritoneal macrophages, a cell type with a common lineage to the Kupffer cell, have been shown to possess PPAR but not PPAR (21). The results presented suggest that PPAR does not alter gene expression in Kupffer cells in response to peroxisome proliferators since neither the protein nor mRNA were found in these cells. Since both PPAR-dependent transcriptional regulation and Kupffer cell activation are required for the hyperplastic response and the carcinogenic effect of peroxisome proliferators, these results also demonstrate the need for in vivo model systems to delineate the mechanisms of peroxisome proliferator-induced hepatocarcinogenesis. In vitro culture systems that lack functional Kupffer cells are likely to produce equivocal results since interaction between parenchymal and Kupffer cells in vivo is required. Combined, these data are consistent with the hypothesis that parenchymal cells respond to Kupffer cell-derived TNF through mechanisms dependent on PPAR expressed in parenchymal cells.

	Notes

 
² To whom correspondence should be addressed at Center for Molecular Toxicology, The Pennsylvania State University, 226 Fenske Laboratory, University Park, PA 16802, USA Email: jmp21{at}psu.edu

^* The first two authors contributed equally to this work.

	References

Top Abstract Introduction References

 

1. Lazarow,P.B. and DeDuve,C. (1976) A fatty acyl CoA oxidizing system in rat liver peroxisomes: enhancement by clofibrate, a hypolipidemic drug. Proc. Natl Acad. Sci. USA, 73, 2043–2046.[Abstract/Free Full Text]
2. Reddy,J.K., Lalwani,N.D., Qureshi,S.A., Reddy,M.K. and Moehle,C.M. (1984) Induction of hepatic peroxisome proliferation in nonrodent species, including primates. Am. J. Pathol., 114, 171–183.[Abstract]
3. Peters,J.M., Cattley,R.C. and Gonzalez,F.J. (1997) Role of PPAR in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator WY-14,643. Carcinogenesis, 18, 2029–2033.[Abstract/Free Full Text]
4. Fahl,W.E., Lalwani,N.D., Watanabe,T., Goel,S.K. and Reddy,J.K. (1984) DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug-induced liver peroxisomes. Proc. Natl Acad. Sci. USA, 81, 7827–7830.[Abstract/Free Full Text]
5. Marsman,D.S., Cattley,R.C., Conway,J.G. and Popp,J.A. (1988) Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res., 48, 6739–6744.[Abstract/Free Full Text]
6. Peters,J.M., Aoyama,T., Cattley,R.C., Nobumitsu,U., Hashimoto,T. and Gonzalez,F.J. (1998) Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. Carcinogenesis, 19, 1989–1994.[Abstract/Free Full Text]
7. Gerbracht,U., Bursch,W., Kraus,P., Putz,B., Reinacher,M., Timmermann-Trosiener,I. and Schulte-Hermann,R. (1990) Effects of hypolipidemic drugs nafenopin and clofibrate on phenotypic expression and cell death (apoptosis) in altered foci of rat liver. Carcinogenesis, 11, 617–624.[Abstract/Free Full Text]
8. Bayly,A.C., Roberts,R.A. and Dive,C. (1994) Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin. J. Cell Biol., 125, 197–203.[Abstract/Free Full Text]
9. Marsman,D.S., Goldsworthy,T.L. and Popp,J.A. (1992) Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell replication for the hepatocarcinogens WY-14,643 and clofibric acid. Carcinogenesis, 15, 1011–1017.
10. Gonzalez,F.J., Peters,J.M. and Cattley,R.C. (1998) Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activated receptor alpha. J. Natl Cancer Inst., 90, 1702–1709.[Abstract/Free Full Text]
11. Rose,M.L., Rusyn,I., Bojes,H.K., Germolec,D.R., Luster,M.I. and Thurman,R.G. (1999) Role of Kupffer cells in peroxisome proliferator-induced hepatocyte proliferation. Drug Metab. Rev., 31, 87–116.[Web of Science][Medline]
12. Rose,M.L., Germolec,D.R., Schoonhoven,R. and Thurman,R.G. (1997) Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. Carcinogenesis, 18, 1453–1456.[Abstract/Free Full Text]
13. Rose,M.L., Germolec,D.R., Arteel,G.E., Schoonhoven,R. and Thurman,R.G. (1997) Dietary glycine prevents increases in hepatocyte proliferation caused by the peroxisome proliferator WY-14,643. Chem. Res. Toxicol., 10, 1198–1204.[Web of Science][Medline]
14. Bojes,H.K., Germolec,D.R., Simeonova,P., Bruccoleri,A., Luster,M.I. and Thurman,R.G. (1997) Antibodies to tumor necrosis factor prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643. Carcinogenesis, 18, 669–674.[Abstract/Free Full Text]
15. Rusyn,I., Tsukamoto,H. and Thurman,R.G. (1998) WY-14,643 rapidly activates nuclear factor B in Kupffer cells before hepatocytes. Carcinogenesis, 19, 1217–1222.[Abstract/Free Full Text]
16. Rose,M.L., Rivera,C.A., Bradford,B.U., Graves,L.M., Cattley,R.C., Schoonhoven,R., Swenberg,J.A. and Thurman,R.G. (1999) Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators. Carcinogenesis, 20, 27–33.[Abstract/Free Full Text]
17. Smedsrod,B. and Pertoft,H. (1985) Preparation of pure hepatocytes and reticuloendothelial cells in high yield from a single rat liver by means of Percoll centrifugation and selective adherence. J. Leukoc. Biol., 38, 213–230.[Abstract]
18. Doolittle,M., Bohman,R., Durstenfeld,A. and Cascarano,J. (1987) Identification and characterization of liver nonparenchymal cells by flow cytometry. Hepatology, 7, 696–703.[Web of Science][Medline]
19. Hays,W.S., Wheeler,D.E., Eghtesad,B., Glew,R.H. and Johnston,D.E. (1998) Expression of cytosolic ß-glucosidase in guinea pig liver cells. Hepatology, 28, 163.
20. Lemberger,T., Staels,B., Saladin,R., Desvergne,B., Auwerx,J. and Wahli,W. (1994) Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J. Biol. Chem., 269, 24527–24530.[Abstract/Free Full Text]
21. Ricote,M., Li,A.C., Willson,T.M., Kelly,C.J. and Glass,C.K. (1998) The peroxisome proliferator-activated receptor- is a negative regulator of macrophage activation. Nature, 391, 79–82.[Medline]
22. Lee,S.S., Pineau,T., Drago,J., Lee,E.J., Owens,J.W., Kroetz,D.L., Fernandez-Salguero,P.M., Westphal,H. and Gonzalez,F.J. (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol., 15, 3012–3022.[Abstract]
23. Dieter,P., Schulze-Specking,A. and Decker,K. (1986) Differential inhibition of prostaglandin and superoxide production by dexamethasome in primary cultures of rat Kupffer cells. Eur. J. Biochem., 159, 451–457.[Web of Science][Medline]

Received August 2, 1999; revised October 13, 1999; accepted November 8, 1999.

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