Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (2024)

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Volume 22 Issue 3 March 2001

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  • Introduction

  • Materials and methods

  • Results

  • Discussion

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Jeffrey W. Lawrence

1Department of Safety Assessment, Merck Research Laboratories, Merck and Co. Inc., Sumneytown Pike, WP45A-201, West Point, PA 19486, USA

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Gordon K. Wollenberg

1Department of Safety Assessment, Merck Research Laboratories, Merck and Co. Inc., Sumneytown Pike, WP45A-201, West Point, PA 19486, USA

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John G. DeLuca

1Department of Safety Assessment, Merck Research Laboratories, Merck and Co. Inc., Sumneytown Pike, WP45A-201, West Point, PA 19486, USA

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Carcinogenesis, Volume 22, Issue 3, March 2001, Pages 381–386, https://doi.org/10.1093/carcin/22.3.381

Published:

01 March 2001

Article history

Received:

24 July 2000

Revision received:

16 November 2000

Accepted:

20 November 2000

Published:

01 March 2001

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    Jeffrey W. Lawrence, Gordon K. Wollenberg, John G. DeLuca, Tumor necrosis factor α is not required for WY14,643-induced cell proliferation, Carcinogenesis, Volume 22, Issue 3, March 2001, Pages 381–386, https://doi.org/10.1093/carcin/22.3.381

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It has been proposed that the cytokine tumor necrosis factor α (TNFα) stimulates peroxisome proliferator-induced hepatic cell proliferation. To test this hypothesis, induction of peroxisome proliferation and hepatocyte proliferation were compared in wild-type C57Bl/6 and TNFα knockout mice. Animals were dosed with either vehicle or 100 mg/kg/day WY14,643 by oral gavage for 4 days. Liver to brain weight ratios increased in both wild-type and TNFα knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNFα knockout mice displayed marked hepatic induction of fatty acyl-CoA oxidase activity (~8-fold) and mRNA content (~5-fold). Electron microscopic examination confirmed increased numbers of peroxisomes in hepatocytes in both mouse models. Moreover, WY14,643 markedly induced hepatic cell proliferation (~15-fold) in both wild-type C57Bl/6 and TNFα knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNFα mRNA was observed in wild-type mice after treatment with WY14,643. These results suggest that the hepatocellular proliferation induced after peroxisome proliferator treatment occurs independently of TNFα signaling.

BrdU, bromodeoxyuridine, FACO, fatty acyl-CoA oxidase, FAM, 6-carboxyfluorescein, 4F1G, 4% neutral buffered formalin and 1% gluteraldehyde, IL-6, interleukin-6, LPS, lipopolysaccharide, PPARα, peroxisome proliferator-activated receptor α, TEM, transmission electron microscopy, TNFα, tumor necrosis factor α, TNF R, TNF receptor.

Introduction

Peroxisome proliferators are a diverse group of chemicals that include plasticizers, herbicides and pharmaceutical hypolipidemic agents (1). Upon administration of these agents to rodents characteristic changes occur in the liver that include hepatomegaly, an increase in the size and number of peroxisomes, hepatic cell proliferation and the induction of hepatocarcinogenesis after long-term administration (2). It is thought that the hepatocarcinogenesis is related to the increased oxidative stress resulting from increased oxidative metabolism and/or the increased cell proliferation observed after peroxisome proliferator treatment (3,4).

Peroxisome proliferators mediate their effects through interaction with a nuclear ligand-dependent transcription factor called peroxisome proliferator-activated receptor α (PPARα) (5). PPARα knockout mice lack the characteristic responses to peroxisome proliferators, including hepatomegaly, proliferation of peroxisomes, increased hepatic cell proliferation and hepatocarcinogensis (6,7).

Previous in vitro and in vivo studies have shown that tumor necrosis factor α (TNFα) is involved in regenerative growth after partial hepatectomy. For example, treatment of rats with an anti-TNFα antibody prevented the mitogenic response after partial hepatectomy (8). In addition, mice lacking the type 1 TNF receptor (TNF R) were deficient in the regenerative response after partial hepatectomy (9) and liver regeneration seen after CCl4-induced hepatic necrosis (10). When TNFα was incubated with murine hepatocytes in culture, a mitogenic response was observed (11). These studies demonstrated that TNFα plays a role in hepatocellular proliferation and liver mass homeostasis.

A current hypothesis suggests that TNFα mediates the mitogenic response induced by peroxisome proliferators (12). According to this hypothesis, peroxisome proliferator-activated Kupffer cells would synthesize and secrete TNFα, which stimulates neighboring hepatocytes to proliferate. Rose et al. (13) demonstrated that peroxisome proliferators could activate Kupffer cells in vivo and in vitro. Inactivation of Kupffer cells with either dietary glycine or methylpalmitate prevented peroxisome proliferator-induced cell proliferation in rats (14, 15). In addition, TNFα mRNA was observed to be increased 2- to 2.5-fold by WY14,643 treatment in rats (12,15). Treatment of rats with anti-TNFα polyclonal antibody also prevented WY14,643-induced cell proliferation (12). In an attempt to directly test the requirement for TNFα in peroxisome proliferator-induced cell proliferation, wild-type C57Bl/6 and TNFα knockout mice, a genetically engineered mouse line that has had the gene for TNFα disrupted, were treated with WY14,643 for 4 days and hepatic peroxisome induction and cell proliferation were assessed.

Materials and methods

Experimental design

C57Bl/6 wild-type male mice were purchased from Charles River Laboratories (Raleigh, NC) and were 10 weeks old and weighed between 24 and 26 g. TNFα knockout male mice (16) were obtained from Dr George Kollias (Hellenic Pasteur Institute, Athens, Greece). The knockout mice used in the study were ~29 weeks old and weighed between 32 and 42 g. The phenotype of the six founder knockout mice was confirmed by demonstrating the absence of an elevation in plasma TNFα concentrations 90 min after lipopolysaccharide (LPS) treatment (data not shown). All mice were individually housed in plastic boxes in a climate controlled room. PMI Certified Rodent Chow and water were available ad libitum. Ten mice of both genetic backgrounds were implanted s.c. with osmotic minipumps containing 50 mg/ml bromodeoxyuridine (BrdU) and five mice from each background were dosed for 4 days with either vehicle (0.5% methylcellulose) or 100 mg/kg/day WY14,643 (Chemsyn Science Laboratories, Lenexa, KS). This dose of WY14,643 has been shown to stimulate cell proliferation and lead to tumor formation in both rats and mice (17). At necropsy, terminal body weights, liver weights and brain weights were determined. A section from the left lateral lobe of the liver from each animal was fixed in 4% neutral buffered formalin and 1% gluteraldehyde (4F1G) for transmission electron microscopy (TEM), 10% formalin overnight followed by 70% ethanol for immunohistochemistry or frozen at –70°C for fatty acyl-CoA oxidase (FACO) activity and mRNA analysis. All animal care and treatment procedures were approved by the Merck Research Laboratories Institutional Animal Care and Use Committee.

Cell proliferation analysis

BrdU was detected immunohistochemically by staining formalin-fixed wax-embedded sections of liver by an indirect avidin–biotinylated peroxidase technique using rat monoclonal anti-BrdU IgG (Accurate, Westbury, NY) as previously described (18). Briefly, tissue sections were post-fixed in zinc-buffered formalin and then incubated in 0.04% pepsin (Sigma, St Louis, MO) in 0.1 N HCl for 25 min at room temperature. The sections were then denatured in 4 M HCl and neutralized in a solution of 0.1 M borax, pH 8.5. Antibody binding and detection were then performed using diaminobenzadine tetrahydrochloride as the chromogen, which stains brown. Digital images were obtained using the Bioquant/TCW capture software (R&M Biometrics, Nashville, TN) and randomly scanning 20 fields throughout sections of the right lateral lobe from each animal in each dose group (40× objective) as previously described (19,20). The images were then subject to analysis with CHRIS software (Sverdrup Technologies, Fort Walton Beach, FL) to determine the total number of hepatocyte nuclei and the number of nuclei that stained positive for BrdU and the percent labeling index calculated for each animal.

Electron microscopy

4F1G-fixed 1 mm3 sections of liver were post-fixed in 2% osmium tetroxide and then embedded in epoxy resin. Ultrathin sections were cut on a Reichert Ultracut S ultramicrotome, stained with uranyl acetate and lead citrate and viewed on a Philips CM12 transmission electron microscope.

FACO activity

FACO activity was assayed by monitoring the evolution of H2O2 according to the procedure of Poosch and Yamazaki (21) using lauryl-CoA as the substrate and 1 mM hydroxyphenylacetic acid as the indicator. Incubations were carried out at 37°C and stopped with 2 mM KCN in carbonate buffer after 10 min. All samples were assayed in duplicate with a corresponding blank (lacking lauryl-CoA) subtracted. Results were converted to nmol product by comparison with a H2O2 standard curve and normalized to mg protein.

RNA analysis

Total RNA was isolated by a combination of Triazol (Gibco, Rockville, MD) extraction and solid phase extraction using a kit from Qiagen (Valencia, CA). Briefly, 100 mg of liver tissue was hom*ogenized in 1 ml of Triazol. To a 0.3 ml aliquot, 60 μl of chloroform was added and the mixture was centrifuged at 10 000 g for 15 min at 4°C. The supernatant was removed and processed using a Qiagen RNeasy RNA isolation kit. The RNA was quantified by spectrophotometic determination at 260 nm. cDNA synthesis was performed in 25 μl with 0.1 μg total RNA with a Taqman RT kit (PE Applied Biosystems, Foster City, CA) at 25°C for 10 min, 48°C for 30 min and 95°C for 5 min. After reverse transcription, a 3 μl aliquot was transferred into each of two 25 μl Taqman amplification reactions containing primer/probe sets for 18S rRNA (6-carboxy-4′,5′-dichloro-2′,7′-dimethylfluorescein tagged) and either mouse FACO or TNFα [6-carboxyfluorescein (FAM) tagged] and amplified at 50°C for 2 min and 95°C for 10 min and at 95°C for 15 s and 60°C for 1 min for 40 cycles on a ABI Prism 7700 Sequence Detection System following the manufacturer's instructions (PE Applied Biosystems). The specific sequences of the primers and probes were

FACO: F primer, 5′-GAG TGA GCT GCC TGA GCT TCA; R primer, 5′-AAG CTA TGG TCG TAA CCG A; probe, 5′-TAMRA-CCC TCA CAG CTG GGC TGA AGG CT-FAM

TNFα: F primer, 5′-AGG AAT GAG AAG AGG CTG AGA CAT; R primer, 5′-CCT TGA CCG TCT TCT CCG GT; probe, 5′-TAMRA-CCG CCT GGA GTT CTG GAA GCC C-FAM

TNFα mRNA levels were not assessed in TNFα knockout animals due to the design of the primer/probe sets.

Results

To directly test the requirement for TNFα in peroxisome proliferator-induced cell proliferation, measures of peroxisome proliferation and cell proliferation were assessed in wild-type and TNFα knockout mice after treatment with 100 mg/kg/day WY14,643 for 4 days. Both wild-type C56Bl/6 and TNFα knockout mice showed similar levels of hepatomegaly after WY14,643 treatment (Figure 1). Relative liver weights appeared lower in untreated TNFα knockout mice compared with untreated wild-type mice. Histological assessment demonstrated that both wild-type and TNFα knockout mice displayed hepatocellular hypertrophy after WY14,643 treatment (data not shown). In addition, FACO activity and FACO mRNA were increased to similar levels in both wild-type and TNFα knockout mice (Figure 2A and B). Peroxisome proliferation was confirmed by ultrastructural examination of liver sections that showed that both wild-type and TNFα knockout mice given WY14,643 had increases in the size and number of hepatic peroxisomes relative to their respective controls (Figure 3).

To measure cell proliferation, mice were implanted with BrdU-containing minipumps and hepatocytes that underwent S phase DNA synthesis were identified by immunohistochemical detection of BrdU incorporation into nuclei. Photomicrographs demonstrated that a greater number of hepatocytes had undergone DNA synthesis after treatment with WY14,643 in both wild-type and TNFα knockout mice than in the respective control mice (Figure 4). Both untreated wild-type and TNFα knockout mice had low basal hepatocyte labeling indices (0.6 and 0.8%, respectively). WY14,643 treatment induced a 15-fold increase in the labeling index in both wild-type and TNFα knockout mice (Figure 5). Consistent with the increased hepatocellular proliferation stimulated by WY14,643, two of five wild-type and three of five TNFα knockout mice treated with WY14,643 had a slight increase in the number of mitotic hepatocytes (data not shown).

To determine if synthesis of TNFα was stimulated by WY14,643 treatment in wild-type mice, TNFα mRNA levels were measured in the livers of these mice. Other groups have reported that hepatic TNFα mRNA levels were increased after WY14,643 treatment of rats (12), however, in our study TNFα mRNA levels decreased with WY14,643 treatment in wild-type mice (Figure 6).

Discussion

In this study we have tested the hypothesis that TNFα is required for the hepatocellular proliferation observed after peroxisome proliferator treatment. The basis for this hypothesis is the reported inhibitory effects of anti-TNFα antibodies on WY14,643-induced hepatocellular proliferation in rats (12). In an attempt to directly test this hypothesis, we treated wild-type C57Bl/6 and TNFα knockout mice with WY14,643 for 4 days. The markers of peroxisome proliferation that were examined, including FACO activity, FACO mRNA and liver enlargement, were increased to equivalent levels by WY14,643 in both wild-type and TNFα knockout mice. Likewise, morphological evaluation demonstrated increases in the size and number of peroxisomes in hepatocytes from mice of both genotypes. In addition, hepatocyte proliferative responses of both wild-type and TNFα knockout mice were similarly increased by WY14,643 treatment. Lastly, we observed a decrease in TNFα mRNA levels in wild-type mice after WY14,643 treatment. These data suggest that TNFα is not involved in the pleiotropic response of rodent liver to peroxisome proliferators.

TNFα knockout mice had 23% smaller livers compared with wild-type mice. This is consistent with the reported role of TNFα in liver growth (8,9). Still, the liver weight changes that occurred after WY14,643 treatment resulted in relative liver weights that were equivalent to those in wild-type mice treated with WY14,643. The liver enlargement could be due to both increased cell size and cell number.

Our data demonstrate that peroxisome proliferator-induced hepatic mitogenesis can occur independently of TNFα and that TNFα may not be required for this event. This is supported by the fact that even though TNFα knockout mice have no detectable levels of TNFα, even after LPS treatment (data not shown), they still respond with marked hepatocellular proliferation to WY14,643 treatment. Moreover, in wild-type mice we observed a decrease in TNFα mRNA after treatment with WY14,643, in direct contrast to results reported in the literature for WY14,643-treated rats (12). The studies reported by Bojes et al. differed from our studies in several ways. In the previous studies a rat model was used with a polyclonal antibody to neutralize TNFα activity in vivo and cell proliferation was monitored only over the first 24 h. It is possible that treatment with anti-TNFα antibody simply delayed the induction of cell proliferation, making it appear as if the antibody blocked the cell proliferation response, when, in fact, it might have occurred with prolonged treatment. Alternatively, the absence of TNFα during in utero and neonatal development may have led to the elaboration of compensatory pathways that are either minor or non-existent in normal animals. This possibility could be tested by the generation of conditional TNFα knockouts or with longer term neutralizing antibody studies.

In studies examining the role of TNFα in acetaminophen toxicity a paradox was observed between studies using TNFα knockout mice and studies that neutralized TNFα with anti-TNFα antibodies. Neutralizing TNFα with an antibody protected wild-type mice from acetaminophen toxicity whereas acetaminophen toxicity was exaggerated in TNFα knockout mice (22). In other models of regenerative hyperplasia, such as occurs after CCl4-induced hepatic necrosis, a clear role for TNFα was demonstrated using TNF R1 knockout mice (10). TNF R1 knockout mice demonstrated severely limited hepatocyte DNA synthesis compared with either TNF R2 knockout or wild-type control mice after treatment with CCl4, even though equivalent liver injury was observed in both models. In partial hepatectomy models of liver regeneration, TNF R1 knockout mice displayed a marked reduction in hepatocellular proliferation (9). Anti-TNFα antibodies also inhibited cell proliferation after partial hepatectomy in rats (8), consistent with the findings from the TNF R1 knockout mice. Thus, while some inconsistency in response between TNFα antibody and TNFα-deficient models for hepatotoxicity end points is apparent, these two models have consistent results regarding mitogenic end points. Our data suggest that even though TNFα is important for some types of hepatic mitogenesis, like those observed after partial hepatectomy and CCl4 treatment, the mechanism of hepatocellular proliferation after peroxisome proliferator treatment appears to be different. This suggestion is consistent with reports that interleukin-6 (IL-6)-deficient mice also elicit a cell proliferation response after peroxisome proliferator treatment that is equivalent to wild-type mice (23). IL-6 knockout mice also have deficiencies in hepatic regeneration after partial hepatectomy (24). Furthermore, adding exogenous IL-6 relieves the deficiency in liver regeneration found in TNF R1 knockout mice (9). Anderson et al. (25) and Corton (personal communication) have found that mice with defects in TNF R1 or TNF R2 or both also retain the mitogenic response after peroxisome proliferator treatment. These studies are consistent with our findings and confirm the lack of a requirement for TNFα in peroxisome proliferator-induced hepatic cell proliferation.

In summary, we have shown that mice that lack TNFα have equivalent peroxisome and cell proliferation induction in response to peroxisome proliferator treatment, indicating that in knockout animals TNFα is not required for peroxisome proliferator-induced hepatic mitogenesis. These data also suggest that the mitogenic response observed after peroxisome proliferator treatment may occur via a mechanism distinct from that of liver regeneration after partial hepatectomy or CCl4 treatment.

Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (3)

Fig. 1.

Effects of WY14,643 on hepatomegaly induction in wild-type C57Bl/6 and TNFα knockout mice. Wild-type (+/+) or TNFα knockout (–/–) mice were dosed with 100 mg/kg/day WY14,643 for 4 days. Livers were removed and weighed. Data are expressed as mean percent brain weights ± SEM.

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Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (4)

Fig. 2.

Effects of WY14,643 on FACO activity and mRNA induction in wild-type C57Bl/6 and TNFα knockout mice. Wild-type (+/+) or TNFα knockout (–/–) mice were dosed with 100 mg/kg/day WY14,643 for 4 days. (A) Livers were hom*ogenized and FACO activity levels assessed as described in Materials and methods. Data are expressed as means ± SEM. (B) Total RNA was isolated and FACO mRNA was quantified by real time RT–PCR as described in Materials and methods. Data are expressed as means ± SEM relative to wild-type control induction.

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Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (5)

Fig. 3.

Effects of WY14,643 on peroxisome proliferation induction in wild-type C57Bl/6 and TNFα knockout mice. Wild-type or TNFα knockout mice were dosed with 100 mg/kg/day WY14,643 for 4 days. Liver sections were removed, fixed and processed for TEM analysis as described in Materials and methods.

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Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (6)

Fig. 4.

Immunohistochemical localization of BrdU incorporation in nuclei in liver sections from wild-type C57Bl/6 and TNFα knockout mice treated with 100 mg/kg/day WY14,643 for 4 days. Livers were removed, fixed and then BrdU was detected as described in Materials and methods.

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Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (7)

Fig. 5.

Effects of WY14,643 on hepatocellular proliferation in wild-type C57Bl/6 and TNFα knockout mice. Wild-type (+/+) or TNFα knockout (–/–) mice were dosed with 100 mg/kg/day WY14,643 for 4 days. The percent labeling index was calculated as described in Materials and methods. Data are expressed as means ± SEM.

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Tumor necrosis factor α is not required for WY14,643-induced cell proliferation (8)

Fig. 6.

Effects of WY14,643 on TNFα mRNA expression in wild-type C57Bl/6 mice. Wild-type mice were dosed with 100 mg/kg/day WY14,643 for 4 days. Total RNA was isolated and TNFα mRNA was quantified by real time RT–PCR as described in Materials and methods. Data are expressed as means ± SEM.

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1

To whom correspondence should be addressedEmail: jeff_lawrence@merck.com

The authors gratefully acknowledge the technical assistance of David Alberts, Gary Dysart, John Frank, Brenda Givler, Karen MacNaul, Carol McCoy and Marcia Pitzenberger. We also thank Drs David Moller and George Kollias for help in obtaining the TNFα knockout mice. We are grateful to Dr Chris Corton for his permission to cite his group's work as a personal communication. In addition, we thank Drs Karen Richards and Tom Rushmore for the use of equipment and Dr Scott Grossman for helpful suggestions.

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© Oxford University Press

Topic:

  • cytokine
  • tumor necrosis factors
  • signal transduction
  • cell proliferation
  • acyl coenzyme a
  • bromodeoxyuridine
  • cell nucleus
  • hepatocytes
  • mice, inbred c57bl
  • mice, knockout
  • peroxisome
  • rna, messenger
  • brain
  • liver
  • mice
  • tube feeding
  • knockout animals
  • oxidase

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Cancer Biology

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