Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824
Received June 30, 2003; accepted October 14, 2003
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ABSTRACT |
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Key Words: acrolein; hepatocytotoxicity; NF-B; PPAR
; prostaglandin.
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INTRODUCTION |
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Sensitivity of liver to allyl alcohol is increased by inflammation, such that hepatic damage is observed at smaller doses. Indeed, in animals treated with a small dose of bacterial lipopolysaccharide (LPS) that alone did not cause liver toxicity but did initiate an inflammatory response, a normally nontoxic dose of allyl alcohol produced overt hepatotoxicity (Sneed et al., 1997). Several inflammatory mediators have been identified that contribute to the LPS-mediated enhancement of allyl alcohol-induced toxicity. Inhibition of Kupffer cell function with gadolinium chloride abolished injury, suggesting that these cells are critical to the response (Sneed et al., 1997
). Neutrophils (PMNs) are also important to injury from LPS/allyl alcohol, as evidenced by the protective effect of PMN depletion (Kinser et al., 2004
). LPS-stimulated Kupffer cells and PMNs release lipid mediators such as prostaglandins (PGs) and thromboxane, the synthesis of which is catalyzed by the enzyme cyclooxygenase-2 (COX-2). COX-2 mRNA in liver tissue and the plasma concentration of PGD2 were increased in rats treated with small doses of LPS and allyl alcohol. In addition, a selective inhibitor of COX-2 protected rats from hepatotoxicity induced by cotreatment with LPS and allyl alcohol (Ganey et al., 2001
). These results suggest an essential role for COX-2 products in LPS-mediated enhancement of allyl alcohol liver injury. PGD2, but not PGE2, increased the cytotoxicity of allyl alcohol in isolated hepatocytes (Ganey et al., 2001
), raising the possibility that the former mediator contributes to injury in vivo.
PGD2 spontaneously dehydrates in aqueous solutions to form PGJ2, which is further metabolized sequentially to 12-PGJ2 and 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) (Fitzpatrick and Wynalda, 1983
). Although PGD2 affects cellular function by binding to plasma membrane receptors, the DP receptor and CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) (Hirai et al., 2001
), no plasma membrane receptors have been identified for PGs of the J2 series. PGJ2 and its metabolites are endogenous ligands for the nuclear peroxisome proliferator-activated receptor-
(PPAR
) (Forman et al., 1995
), and binding to this receptor effects functional changes in cells. Of these PGs, 15d-PGJ2 has the greatest affinity for the receptor. Not all actions of 15d-PGJ2 are mediated through PPAR
, however, as evidenced by the observations that other PPAR
agonists do not mimic all of the effects of 15d-PGJ2 and that 15d-PGJ2 produces some of the same effects in cells with and without PPAR
(Castrillo et al., 2000
; Guyton et al., 2001
; Hortelano et al., 2000
; Straus et al., 2000
). 15d-PGJ2 inhibits the activation of the transcription factor, NF-
B (Castrillo et al., 2000
; Guyton et al., 2001
; Hortelano et al., 2000
; Straus et al., 2000
), and this inhibition may contribute to some of the observed actions of 15d-PGJ2.
The purpose of these studies was to examine further the enhancement of allyl alcohol-induced cytotoxicity by PGD2. Specifically, the role of the PGD2 metabolite 15d-PGJ2 was evaluated, and studies designed to investigate its mechanism of action were undertaken.
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MATERIALS AND METHODS |
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Animals and hepatocyte isolation.
Male, Sprague-Dawley rats (Crl:CD (SD)IGS BR; Charles River, Portage, MI), weighing 125175 g were used for hepatic parenchymal cell isolation. Rats received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23, revised 1985). They were housed under conditions of controlled temperature, humidity, and light (12 h dark:12 h light) and were allowed food (Harlan Teklad Rodent Diet 8640) and water ad libitum.
Hepatocytes were isolated from the livers of rats by collagenase perfusion using a modification of the method of Seglen (1973) as described previously (Ganey et al., 1994). Hepatocyte preparations were >85% viable as determined by exclusion of trypan blue. Cells were placed in Williams medium E supplemented with 10% fetal calf serum and 0.5 mg/ml gentamicin and plated either in 96-well tissue culture plates at a density of 1.2 x 104 cells per well, in 24-well tissue culture plates at a density of 1.0 x 105 cells per well, or in 100-mm tissue culture dishes at a density of 2.5 x 106 cells per dish. After a 2- to 3-h adherence period at 37°C, the medium was removed and replaced with Williams medium E supplemented only with 0.5 mg/ml gentamicin.
Assessment of cytotoxicity and effects of pharmacologic agents.
Cells were exposed to various compounds for 03 h at 37°C (see figure legends for details) before addition of allyl alcohol (0100 µM) or acrolein (0125 µM). They were then incubated for 90 min at 37°C. Hepatocellular injury was assessed by measuring the release of alanine aminotransferase (ALT) into the medium. Release of ALT correlates with other measures of cytotoxicity in hepatocytes, such as uptake of trypan blue (Ganey et al., 1994). After 90 min exposure of cells to allyl alcohol or acrolein, 50 µl of the medium was transferred to a clean 96-well plate. The remaining medium was aspirated, and the cells were lysed with a 1.0% solution of Triton X-100. The activity of ALT was determined in both the medium and lysates using Sigma Diagnostics kit no. 59. The total cellular ALT activity was calculated from the activity in the medium plus the activity in the lysate, and hepatocellular injury is presented as the percentage of total cellular ALT released into the medium.
Measurement of cAMP.
Hepatocytes were plated in 10-cm tissue culture dishes and exposed to 50 µM IBMX for 2 h at 37°C. Supernatants were then aspirated, and 2.5 ml of 0.1 M HCl was added to the cells remaining on the plate. Cells were incubated for 15 min at room temperature, scraped off the plates, and triturated with a pipettor until homogenized. The homogenate was spun at 1000 x g for 10 min, and the supernatant was decanted to a clean tube and stored at -80°C until assayed. cAMP activity was measured in acetylated samples by commercial EIA (Cayman Chemical) according to manufacturers instructions.
Protein synthesis.
Hepatocytes were plated in 24-well plates and allowed to adhere for 23 h in Williams medium E containing 10% FBS. The medium was replaced with leucine-free RPMI supplemented with 3H-leucine (1 mCi/ml) and 0.5 mg/ml gentamicin. Prostaglandins (1050 µM) or cycloheximide (7 mM) were added 15 min later, and cells were incubated at 37°C for 2 h. Cells were then treated with allyl alcohol (25100 µM) and further incubated for 1.5 h. After this treatment, medium was removed, and ALT activity in the medium was measured. Adherent hepatocytes were rinsed once with ice-cold, phosphate-buffered saline (PBS) and lysed with 0.1% Triton X-100. Proteins were precipitated from the lysate with an equal volume of ice-cold 10% trichloracetic acid. The precipitate was washed three times with 10% trichloracetic acid and solubilized with 1 ml 1.0 N NaOH overnight at room temperature. Scintillation fluid was added, and 3H levels were quantified [counts per minute (cpm)] using a liquid scintillation counter.
NF-B electrophoretic mobility shift assay (EMSA).
After treatment hepatocytes were washed with ice-cold PBS, dislodged from plates with cell scrapers, and resuspended (1 x 106 cells) in 400 µl hypotonic lysis buffer A (10 mM HEPES pH 7.9, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1.0 mM dithiothreitol (DTT), and 0.5 mM PMSF). Cells were allowed to incubate on ice in buffer A for 15 min before solubilization in 25 µl 10% Igepal (Sigma Chemical Co., St. Louis, MO) and vortexing. Nuclei were collected by centrifugation at 15,000 x g for 30 s. The nuclear pellet was resuspended in 50 µl high-salt extraction buffer B (20 mM HEPES, 0.4 M NaCl, 0.1 mM EDTA, 0.1 mM EGTA, 1.0 mM DTT, and 0.5 mM PMSF) and mixed for 15 min at 4°C, and the nuclear extract was obtained after removing the debris by centrifugation for 5 min at 15,000 x g. Nuclear protein concentration was quantified using the Bradford assay (Bio-Rad Laboratories, Hercules, CA).
For the EMSA, double-stranded NF-B oligonucleotide probes were end-labeled with 32P-ATP using T4 polynucleotide kinase (Promega, Madison, WI) and separated from the unincorporated label by minicolumn chromatography (QIAquick, QIAGEN, Inc., Valencia, CA). Nuclear protein (10 µg) was incubated for 30 min on ice with radiolabeled oligonucleotide probes (26 x 104 cpm) in 20 µl reaction buffer containing 1 µg poly(dI-dC), 10 mM TrisHCl, pH 7.8, 40 mM KCl, 1 mM EDTA, 1 mM DTT and 10% glycerol. Nucleoprotein-oligonucleotide complexes were resolved by electrophoresis in a 4% nondenaturing polyacrylamide gel. After electrophoresis, gels were dried on 3MM paper in a vacuum dryer and exposed to radiographic film. The oligonucleotide sequence used for the detection of binding activity to the NF-
B site was 5'-AGTTGAGGGGACTTTCCCAGG-3' (Promega). Cold competition assays were conducted by adding a 200-fold molar excess of unlabeled dsDNA oligonucleotide simultaneously with the labeled probe. For supershift assays, p50 antibody (H-119; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and/or p65 antibody (A; Santa Cruz Biotechnology, Inc.) was added to select nuclear protein reaction mixtures before the addition of radiolabeled probe.
Statistical analysis.
Results are presented as the mean ± SEM. Data presented as percentages were first transformed (arcsin square root transformation) before analysis by two-way repeated measures ANOVA. Post hoc comparisons were made using Tukeys test. The criterion for significance was p < 0.05.
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RESULTS |
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15d-PGJ2 has been reported to induce functional changes in macrophages via activating cAMP (Vaidya et al., 1999); therefore, the effect of manipulation of cAMP on the response to 15d-PGJ2 was examined. IBMX is a phosphodiesterase inhibitor that increases cAMP. Incubation with IBMX increased cAMP activity by approximately 80% (data not shown), but did not affect the 15d-PGJ2-mediated enhancement of allyl alcohol cytotoxicity (Fig. 5A
). Similarly, inhibition of cAMP activity with an inactive analog, Rp-cAMPs, did not affect 15d-PGJ2 enhancement of allyl alcohol-induced cell killing (Fig. 5B
).
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DISCUSSION |
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Allyl alcohol-induced toxicity only occurs after bioactivation to acrolein. The sensitivity of hepatocytes to the cytotoxicity of acrolein was also increased by 15d-PGJ2 (Fig. 3), indicating that the effect on cytotoxicity of allyl alcohol cannot be explained simply by increased conversion to acrolein.
The effect of 15d-PGJ2 to increase the sensitivity of hepatocytes to allyl alcohol does not appear to be mediated through the DP receptor, because BW245C, over a range of concentrations including one-hundred times greater than the IC50, did not reproduce the increase in cytotoxicity of allyl alcohol and did not interfere with the ability of 15d-PGJ2 to enhance allyl alcohol-mediated cytotoxicity. PPAR also does not appear to be involved in the 15d-PGJ2-mediated increase in allyl alcohol-induced cell death, because neither a PPAR
-agonist nor a PPAR
antagonist affected the response to allyl alcohol. PPAR
-independent effects of 15d-PGJ2 have been reported previously. For example, in macrophages 15d-PGJ2 inhibited production of tumor necrosis factor-
and thromboxane B2 (Guyton et al., 2001
) and increased production of superoxide anion (Hortelano et al., 2000
) through mechanism(s) independent of PPAR
.
The mechanism by which PGD2 and its metabolites increase the sensitivity of hepatocytes to allyl alcohol-induced cytotoxicity is unknown. In hepatocytes or isolated livers, PGD2 altered the profile of protein phosphorylation, increased release of intracellular calcium, enhanced production of inositol trisphosphate, stimulated glycogen phosphorylase and glucose release, and inhibited gluconeogenesis (Altin and Bygrave, 1988; Casteleijn et al., 1988a
,b
), demonstrating that PGD2 has diverse effects on intracellular signaling and glucose metabolism. A well-known action of PGD2 is to increase intracellular cAMP. Modulation of cell cycle by PGD2 or 15d-PGJ2 has been reported to occur by cAMP-dependent (Okuda-Ashitaka et al., 1990
) and -independent (Hughes-Fulford and Fukushima, 1993
) mechanisms. Furthermore, increasing cAMP through inhibition of phosphodiesterase activity with IBMX enhanced 15d-PGJ2-mediated inhibition of neutrophil adhesion and superoxide anion production (Vaidya et al., 1999
). On the other hand, 15d-PGJ2-induced apoptosis of neutrophils was not dependent on cAMP (Ward et al., 2002
). In the current study, neither increasing cAMP nor inhibiting generation of cAMP affected the increased sensitivity of hepatocytes to allyl alcohol in response to 15d-PGJ2 (Fig. 5
), suggesting that this effect is not dependent on cAMP.
PGD2 affects hepatocellular proteins, and in the current study, both 15d-PGJ2 and allyl alcohol caused concentration-dependent inhibition of protein synthesis (Fig. 6). However, when the same degree of inhibition of protein synthesis that occurred with a concentration of 15d-PGJ2 that enhanced allyl alcohol cytotoxicity was reproduced with cycloheximide, the sensitivity of hepatocytes to allyl alcohol was not altered. This observation indicates that inhibition of protein synthesis is not sufficient for the increased sensitivity to allyl alcohol.
Another mechanism by which 15d-PGJ2 may affect allyl alcohol-induced cell death is through inhibition of activation of the transcription factor, NF-B. In quiescent cells, NF-
B exists in the cytosol in association with an inhibitory protein, I
B. Phosphorylation of I
B results in its ubiquitination and degradation via a proteasome pathway. This activates NF-
B, which is then free to migrate into the nucleus and modulate gene expression. Numerous reports suggest that inhibition of activation of NF-
B permits or induces cell death in response to a variety of agents (Botchkina et al., 1999
; Hatano and Brenner, 2001
; Izban et al., 2001
; Ni et al., 2001
; Russo et al., 2001
). For example, liver injury induced by bile duct ligation was greater in mice in which activation of NF-
B was inhibited compared with mice in which NF-
B was activated (Miyoshi et al., 2001
). In addition, exposure to bile acids that did not activate NF-
B caused death in rat hepatoma cells, whereas cells exposed to bile acids that activated NF-
B survived (Rust et al., 2000
). In particular, 15d-PGJ2 inhibited the activation of NF-
B stimulated by LPS or tumor necrosis factor-
, and this inhibition was associated with cell death (Ward et al., 2002
). Thus, it is clear that inhibition of NF-
B activation can be associated with enhanced tissue injury and cell death.
In the present study, allyl alcohol caused nuclear translocation of NF-B at noncytotoxic concentrations (Fig. 7
), but not at a concentration that resulted in cell death. A similar effect on NF-
B activation was observed in acrolein-treated human lung adenocarcinoma cells (Horton et al., 1999
). The mechanism by which allyl alcohol activates NF-
B was not investigated in the present study; however, allyl alcohol activates PKC
in hepatocytes (Maddox et al., 2003
), and PKC
is critical to NF-
B activation in response to a variety of stimuli (Minami et al., 2003
; Page et al., 2003
; Vancurova et al., 2001
). Thus, it is possible that allyl alcohol activates NF-
B through a PKC
-mediated pathway. The reason why NF-
B was not activated at larger, cytotoxic concentrations of allyl alcohol is unknown. 15d-PGJ2 inhibited nuclear translocation of NF-
B in hepatocytes exposed to allyl alcohol and caused cell death at normally noncytotoxic concentrations of allyl alcohol. Thus, under all conditions in which allyl alcohol induced cell death, activation of NF-
B was inhibited.
It has been reported that 15d-PGJ2 inhibits NF-B through both PPAR
-dependent and -independent mechanisms (Castrillo et al., 2000
; Guyton et al., 2001
; Hortelano et al., 2000
; Straus et al., 2000
). One possible mechanism is through inhibition of I
B degradation (Mullally et al., 2001
; Ward et al., 2002
), which precedes activation of NF-
B (Chen et al., 1995
). Proteasome activity is necessary for the degradation of I
B; thus, inhibition of proteasome activity could contribute to the inhibition of NF-
B activation. Inhibition of proteasome activity with MG132, which prevents activation of NF-
B (Fiedler et al., 1998
; Hellerbrand et al., 1998
), increased the sensitivity of hepatocytes to allyl alcohol as well as to acrolein (Fig. 8
). These results support the hypothesis that inhibition of NF-
B by 15d-PGJ2 contributes to the enhancement of allyl alcohol-mediated cytotoxicity. Alternative mechanisms by which MG132 increases the sensitivity to allyl alcohol cannot be ruled out, however. For example, MG132 increased toxicity of 6-hydroxydopamine in neuronal cells through inhibition of protein degradation (Elkon et al., 2001
).
In summary, the PGD2 metabolites, PGJ2 and 15d-PGJ2, increased the sensitivity of hepatocytes to allyl alcohol-induced cytotoxicity. This effect does not appear to be mediated through the DP receptor or PPAR. Increased cytotoxicity was associated with inhibition of NF-
B activation, and another agent that inhibits activation of this transcription factor also increased the cytotoxicity of allyl alcohol. Taken together, these results suggest that inhibition of NF-
B activation by 15d-PGJ2 contributes to the increased sensitivity to allyl alcohol. The mechanisms by which inhibition of NF-
B leads to enhancement of allyl alcohol-induced cytotoxicity remain to be investigated.
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ACKNOWLEDGMENTS |
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NOTES |
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