* Toxicology Graduate Program,
Department of Veterinary PathoBiology and
Department of Veterinary Diagnostic Medicine, University of Minnesota, St. Paul, Minnesota 55108
Received August 30, 1999; accepted November 8, 1999
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ABSTRACT |
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Key Words: apoptosis; Bfl-1; carbon tetrachloride (CCl4); cytokines; dimethylnitrosamine (DMN); hepatotoxicity; inflammation; necrosis; TNF.
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INTRODUCTION |
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There appears to be a critical role for TNF in various models of hepatotoxicity. For example, carbon tetrachloride (CCl4)-induced hepatotoxicity is blocked by the administration of soluble TNF
receptors (TNFRs) (Czaja et al., 1995
). Liver repair following CCl4 is mediated by TNF
(Bruccoleri et al., 1997
; Yamada and Fausto, 1998
). In cadmium-induced hepatotoxicity, pretreatment with anti-TNF
antibodies prevented focal inflammation as well as secretion of the acute-phase reactant, serum amyloid A (Kayama et al., 1995
), indicating that these processes are cytokine-dependent. Similarly, neutralizing antibodies to TNF
delayed increases in serum levels of IL-1
and liver enzymes as well as shortened the recovery time following acetaminophen treatment (Blazka et al. 1995
; 1996
). Acute inflammatory responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin were mimicked by the administration of exogenous IL-1ß and TNF
(Moos et al., 1994
). Taken together, these data suggest that TNF
contributes to pathological manifestations of chemical-induced liver damage. However, the mechanism by which TNF
controls hepatotoxicity remains undefined.
There are 2 cell surface receptors for TNF of approximately 55 kDa (TNFR-1) and 75 kDa (TNFR-2), each with distinct functions (Tartaglia and Goeddel, 1992
). TNFR-1 and TNFR-2 lack significant homology in the intracellular domains, further suggesting that they are involved in differential signaling pathways. For example, TNFR-1 is responsible for the upregulation of c-fos, IL-6 and manganese superoxide dismutase mRNA, prostaglandin E2 synthesis, surface expression of IL-2 receptor and MHC class I and II molecules, growth inhibition and cell death (Brakebusch et al., 1992
; Engelman et al., 1990; Espevik et al., 1990
; Hohmann et al., 1990
; Kruppa et al., 1992
; Naume et al., 1991
; Shalaby et al., 1990
; Tartaglia et al., 1991
; Thoma et al., 1990
). TNFR-2 signaling seems to be restricted to T-cell proliferation (Grell et al., 1998
; Tartaglia et al., 1991
); however, recent evidence suggests that TNFR-2 mediates migration of Langerhans' cells (Wang et al., 1996
; 1997
).
Dimethylnitrosamine (N-nitrosodimethylamine, DMN) is a member of the family of N-nitroso compounds that has potent hepatotoxicant activity in mammals (Craddock, 1983) and is a suspected carcinogen in humans. Lifetime exposure to nitrosamines occurs via dietary sources (cheeses, and cured meats and fish), alcoholic beverages, and cigarette smoke, as well as in industrial situations. The primary site for DMN metabolism and toxicity is the liver. DMN bioactivation is thought to occur either through the liver mixed-function oxidases (cytochrome P450 2E1) or through hepatic monoamine oxidase (reviewed in Myers and Schook, 1996). The end result is the formation of toxic intermediates such as hydroxyl radicals, reactive oxygen intermediates, and formaldehyde, with the consequence being lipid peroxidation and/or DNA alkylation (Montesano and Bartsch, 1976
). Hepatic centrilobular necrosis has been observed in both mice and humans exposed to DMN.
Molecular mechanisms accounting for DMN-induced hepatotoxicity have been studied. Previously, we have demonstrated that exposure to DMN in vivo induces an acute-phase response for serum amyloids A and P and albumin (Lockwood et al., 1994). DMN exposure also results in a transient increase in serum cytokine levels for IL-1
, TNF
, and IL-6 (Schook et al., 1992
). These data show that DMN exposure is associated with hepatic proinflammatory gene expression. However, previous studies may have suffered from incomplete neutralization of TNF
activity, especially membrane-associated TNF
. Further, there has been no distinction between activities mediated by TNFR-1 versus TNFR-2.
To determine the signaling mechanism for TNF during acute liver injury, strains of TNFR knockout (KO) mice, lacking either TNFR-1, TNFR-2, or both receptors were exposed to vehicle (phosphate-buffered saline [PBS]) or DMN (100 mg/kg) for 24 h. Hepatic histopathological and cellular changes during DMN exposure were examined using TNFR KO mice compared against each TNFR KO strain as well as to TNFR intact wild type (WT) mice. In addition, multi-probe RNase protection assays (RPAs) were used to examine the hepatic cytokine, cytokine receptor and apoptotic gene expression patterns following low- and high-dose acute DMN exposure in WT and TNFR KO mice. Because both DMN and CCl4 are bioactivated to reactive intermediates by cytochrome P450 2E1 (Guengerich, 1987
, 1991; Haggerty and Holsapple, 1990
; Koop, 1992
) and both cause hepatic centrilobular necrosis (Butler and Hard, 1971
; Rechnagel and Glende, 1973
; Reynolds and Ree, 1971
), WT and TNFR KO mice were injected with either DMN or CCl4 in order to further investigate the molecular events associated with TNF
during different xenobiotic exposure regimens. Results suggest that, overall, similar mechanisms exist and TNF
shares a common role during different xenobiotic exposure regimens.
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MATERIALS AND METHODS |
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Histopathology.
A portion of the liver was fixed in 4% buffered paraformaldehyde for 1824 h at 4°C and paraffin embedded. Serial sections (4 µm) were mounted on poly-L-lysine-coated slides, deparaffinized and stained with hematoxylin and eosin for separate analyses of histopathology and cellular infiltration (below).
Histopathological and cellular infiltration analyses.
Blinded liver samples were submitted for histological evaluation and at least 2 sections from each liver were examined. Histopathological evaluation for necrosis included, but was not limited to, assessing the distribution and extent of cell death (hepatocytes and non-parenchymal cells). Lesions were graded on a semiquantitative scale: 0, normal; 1, rare foci of necrotic cells in centrilobular zones (no more than 12 sites per section); 2, few necrotic foci (less than half of centrilobular zones had sites of necrosis); 3, many/diffuse centrilobular zones with necrosis (confined to centrilobular zone only); 4, diffuse centrilobular to midzonal necrosis; and 5, diffuse submassive to massive necrosis (most or almost all of lobule was necrotic).
The extent of inflammatory cellular infiltration into the liver was examined using the same liver samples as for histopathology. Cellular infiltration was graded visually on a semiquantitative scale: 0, no influx; 1, rare inflammatory cells (no more than 13 cells in 1 or 2 centrilobular zones per section); 2, few inflammatory cells (15 cells in less than 50% of centrilobular zones); 3, moderate inflammatory cell infiltration (515 cells in most centrilobular zones); 4, marked inflammatory cell infiltration (greater than 15 cells in most centrilobular to midzonal areas); and 5, severe inflammatory cell infiltration (too numerous to count and infiltrating most of lobule).
RNA extraction.
Liver sections (~200 mg) were quickly thawed and homogenized in 2 ml of TRIZOL (Life Technologies, Grand Island, NY) and total RNA was isolated according to the manufacturer's directions. RNA was resuspended in RNase-free water, quantitated using UV spectrophotometry, and stored at 80°C.
Multi-probe RPAs.
The DNA templates (mCK3, mCR4, mAPO2, and mAPO3), and In Vitro Transcription and RPA kits were purchased from PharMingen (San Diego, CA). Briefly, RNA probes were generated using 1 µg of template DNA and in vitro transcribed using T7 RNA polymerase. Yeast tRNA (10 µg) and PharMingen-supplied mouse control RNA (2 µg) were used as negative and positive controls, respectively. Total liver RNA (1020 µg) was dried and resuspended in 2.44 x 105 cpm/µg and hybridized at 56°C for 1618 h. Following hybridization, RNA samples were RNase A/T1-digested for 45 min at 30°C, followed by incubation with proteinase K for 15 min at 37°C and then ethanol precipitated. Protected RNAs were separated on a 6% polyacrylamide/7 M urea denaturing gel. Following electrophoresis, the gels were dried and exposed to X-ray film or phosphorimager screens and bands were quantitated using densitometry or phosphorimagery, respectively (Molecular Dynamics, Sunnyvale, CA).
Statistical analyses.
All necrosis and cellular infiltration experiments were performed with at least 5 mice and the results are represented as an average ± SE for each mouse strain within each dosing group. The results were analyzed using the Kruskal-Wallis H test, a nonparametric equivalent to a 1-way analysis of variance. A 95% confidence level was used to define statistical significance. The hepatic gene expression data shown is from one group of mice and results are representative for 2 independent, identically treated groups (n = 2).
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RESULTS |
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All vehicle-treated mice had normal liver histology irrespective of TNFR genotype (Fig. 1). Centrilobular and midzonal necrosis was evident in all WT and TNFR KO mice exposed to DMN. Hepatic cords in affected areas were often disrupted and exhibited individualization of hepatocytes. Hepatocytes in affected centrilobular zones were characterized by clumped chromatin, karyorrexis, or nuclear pyknosis, and by hypereosinophilic cytoplasm. In more severely affected areas, there was loss of hepatocytes with centrilobular to midzonal hemorrhage (Fig. 1
).
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All vehicle-treated WT and TNFR KO mice had necrosis and cellular infiltration scores of 0 (data not shown). Necrosis and cellular infiltration scores for mice exposed to DMN (100 mg/kg) are shown in Figure 2. No significant differences in necrosis were observed between WT, TNFR-1 KO, and TNFR DKO mice exposed to DMN. However, TNFR-2 KO mice had significantly (p < 0.05) higher necrosis scores (3.4 ± 0.2) compared to WT (2.6 ± 0.2), TNFR-1 KO (2.4 ± 0.2) and TNFR DKO (2.9 ± 0.1) mice (Fig. 2A
). In addition, 37.5% (3/8) of TNFR-2 KO mice succumbed to DMN-induced death prior to tissue harvest at 24 h post-exposure (dead TNFR-2 KO mice were not included in the scoring procedure). We also observed an almost complete absence of inflammatory cells in TNFR-1 KO and TNFR DKO mice (Fig. 2B
), indicating that TNFR-1 mediates DMN-induced cellular influx into the liver. These infiltrating cells were observed to be mainly neutrophils, macrophages, and T cells (data not shown).
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The proinflammatory cytokines TNF, lymphotoxin (LT)ß, TNF
, IL-6, interferon (IFN)-
, IFN-ß, transforming growth factor (TGF)-ß1 and TGFß2 were analyzed by RPA (Fig. 3
). As expected, LPS increased hepatic transcripts for TNF
and IL-6. At 6-h post-exposure, vehicle-treated animals showed enhanced transcripts for TNFß and TNF
compared to naive and DMN (5.0 mg/kg)-treated mice, and increased IFN-
transcripts as compared to DMN-treated mice. Increased cytokine expression observed following 6 h of vehicle treatment is consistent with a transient increase in inflammatory gene expression that subsides by 24 h (Lockwood et al., 1991
; 1994
; Schook et al., 1992
). Following 24 h of high-dose DMN (100 mg/kg), hepatic expression of TNFß, LTß, TNF
, and IFN-
was induced 3- to 10-fold compared to vehicle controls, with little change in IL-6, IFN-ß, TGFß1, or TGFß2 (Fig. 3
). However, compared to naive mice, only transcripts for TNF
were greatly increased following DMN (100 mg/kg).
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Because cytokines must signal through specific receptors in order to elicit biological effects, proinflammatory cytokine receptor transcript levels were analyzed (Fig. 5). Differences in hepatic cytokine receptor expression in WT mice were not observed between vehicle and DMN (5.0 mg/kg) following a 6-h exposure. In contrast, a high-dose 24-h DMN (100-mg/kg) exposure induced hepatic expression of IL-1RI and IL-1RII, but suppressed gp130 transcripts compared to both naive and vehicle controls (Fig. 5A
). IL-6R
transcripts were not significantly altered during any vehicle or DMN exposure. In contrast to DMN, CCl4 (0.3 or 1.0 ml/kg) was a potent inducer of hepatic cytokine receptor expression in WT mice. Mice treated with CCl4 (0.3 or 1.0 ml/kg) showed upregulated transcripts for IL-1RI, TNFR-2, TNFR-1, IL-6R
, gp130, TGFßRI and TGFßRII at both 6 and 24 h. Interestingly, and in contrast to DMN, CCl4 did not alter expression of IL-1RII (Fig. 5B
). These data further confirm differential effects of cytokine production and signaling in the liver for these 2 hepatotoxicants.
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Compared to vehicle and naive controls, exposure of WT mice to DMN (5.0 mg/kg) for 6 h did not alter hepatic Fas transcripts. In contrast, TNFR DKO mice exposed to DMN (5.0 mg/kg) exhibited a 2.5-fold increase in Fas expression compared to vehicle controls (Fig. 6A). Exposure to high-dose DMN (100 mg/kg) for 24 h increased (1.5- to 1.7-fold) hepatic Fas expression in both WT and TNFR DKO mice compared to vehicle controls.
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Hepatic expression of the Bcl-2 family of genes was measured in WT and TNFR DKO mice exposed to DMN (5.0 or 100 mg/kg) for 6 or 24 h, respectively (Table 1). We observed that naive TNFR DKO mice had 41% fewer relative Bcl-XL transcripts. Hepatic Bcl-XL and Bax expression were increased following low- and high-dose DMN in both WT and TNFR DKO mice, whereas a down-regulated expression (3768%) of Bcl-W was observed at 24 h in both strains of mice. Only minor differences between vehicle and DMN in WT or TNFR DKO were observed for Bfl-1 and Bak (Table 1
). Hepatic Bcl-2 was not detected following vehicle or DMN exposure in either strain (data not shown).
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DISCUSSION |
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In order to understand the cellular and molecular effects of TNF in the liver during acute chemical-induced hepatotoxicity, WT, TNFR-1 KO, TNFR-2 KO and TNFR DKO mice were exposed to high-dose DMN (100 mg/kg). Moreover, acute exposure to another hepatotoxicant, CCl4, was compared at the level of hepatic gene expression. In order to focus on apoptotic genes with minimal necrosis, a dose of 0.3 ml/kg CCl4 was given for 6 h as previously discussed (Shi et al., 1998
). Similarly, a low-dose exposure to DMN (5.0 mg/kg) (Bhattacharjee et al., 1998
; Lockwood et al., 1994
; Myers and Schook, 1996
) was used because necrosis is not detected following 6 h of treatment (manuscript in preparation). A 24 h exposure to CCl4 (1.0 ml/kg) was used to induce hepatic necrosis (Yamada and Fausto, 1998
) with levels comparable to our high-dose DMN (100 mg/kg) exposure regimen (T. D. O'Brien, unpublished results). Hence, we were able to compare both low- and high-dose acute exposures for these xenobiotics to reveal subtle differences in hepatic gene regulation and the role of TNF
.
Previous reports have used antibodies or soluble receptors directed against TNF in order to neutralize its effect (Blazka et al., 1995
; 1996
; Bruccoleri et al., 1997
; Czaja et al., 1995
; Kayama et al., 1995
), but this approach can be problematic because the neutralization may not be 100%, particularly during chronic exposure regimens. Further, the reagents may not neutralize membrane bound TNF
. In addition, because each TNF
receptor has structurally dissimilar intracellular domains (Tartaglia and Goeddel, 1992
), differential receptor signaling may regulate separate hepatotoxic or repair events. Indeed, TNFR-1 appears to be required for the rapid influx of immunocytes into the liver during high-dose, acute DMN exposure. We have used this model to show that immunocyte influx was not required for liver pathology to occur during acute DMN exposures. Our results further suggested that TNFR-1 signals may be detrimental in the liver unless TNFR-2 signals also occur (Fig. 2
). Thus, genetic TNFR KO mice permit the study of TNF
effects with respect to individual receptor signaling events.
Acute exposure to DMN or CCl4 induced a proinflammatory response accompanied by induction of hepatic TNF and IFN-
(Figs. 4 and 5
). Thus, the liver is a potential source for TNF
detected in the serum following low-dose, multiple exposures to DMN (Schook et al., 1992
). In addition, CCl4 rapidly upregulated hepatic expression of TNFR-1 and TNFR-2, whereas the effect of DMN on these transcripts was indistinguishable from vehicle controls (Fig. 5
). Our data further substantiates that TNF
is a key cytokine involved in DMN and CCl4 hepatotoxicity. However, our results also showed that there are subtle, yet critical differences in the hepatic gene expression for these diverse xenobiotics despite a common bioprocessing pathway. This may result from the different bioreactive intermediates that are produced from each compound. Our histological data show that TNFR-1-deficient mice exposed to high-dose DMN lack hepatic cellular infiltration, yet show no reduction in necrosis compared to DMN-treated WT mice (Fig. 2
). However, a previous report observed decreases in both CCl4-mediated hepatotoxicity and inflammation following pretreatment with soluble TNFR (Czaja et al., 1995
). These differences could be related to the high dose (5.0 ml/kg) of CCl4 used in that study, as was previously suggested (Bruccoleri et al., 1997
; Louis et al., 1998
). This high dose of CCl4 could result in extensive hepatic necrosis and TNF
production. In addition, important differences in the metabolites generated from CCl4 and DMN may also influence subsequent TNF
effects. We have also observed differences in TNF
dependence for DMN-mediated hepatotoxicity in acute high-dose DMN (100 mg/kg) versus subacute low-dose DMN (5.0 mg/kg) exposure regimens (manuscript in preparation). Finally, whereas genetic knockouts completely abrogate TNF
signals, it cannot be excluded that soluble TNF
receptors did not completely neutralize TNF
signals; small amounts of TNF
may signal protective responses that are masked in the presence of elevated TNF
signaling. Although we cannot as yet link Bfl-1 expression to hepatotoxicity, it is interesting that CCl4 differed from DMN by upregulating TNFR-1, TNFR-2 and Bfl-1 transcripts, the latter in a TNFR-dependent manner. Thus, our data show differences exist between hepatic cytokine, cytokine receptor, and apoptotic genes following acute DMN and CCl4 exposures, and that the role of TNF
may be more critical for mediating specific pathologic and molecular outcomes in each system.
TNF has been shown to down-regulate P450 activities by decreasing their expression (Ghezzi et al., 1986
; Renton and Armstrong, 1994
; Warren et al., 1999
). Thus, the use of TNFR DKO mice may be problematic because the lack of TNF
signaling could lead to uncontrolled P450-mediated bioactivation of DMN or CCl4 leading to increased hepatotoxicity. However, Boess et al. (1998) have shown that P450 2E1 activity, which is the principle enzyme responsible for the conversion of acetaminophen to its hepatotoxic metabolite (Lee et al., 1996
; Thomsen et al., 1995
), was not altered following acute exposure to acetaminophen (400 mg/kg) in TNF
/LT
double-deficient mice. This would suggest that the lack of TNF signaling does not alter the metabolic machinery during DMN exposure. Our results support this hypothesis, because TNFR DKO mice did not show increased hepatotoxicity following a 24-h DMN (100 mg/kg) exposure compared to WT, TNFR-1 KO and TNFR-2 KO (Fig. 2A
).
Following TNF administration, vascular cell adhesion molecule-1 and E-selectin up-regulation does not occur in TNFR-1 KO mice, as compared to WT mice (Neumann et al., 1996
). TNF
challenge caused mononuclear and neutrophil infiltration in the liver, lungs, and kidneys in WT mice, but not in TNFR-1 KO mice, suggesting that the TNFR-1 is responsible for mediating leukocyte infiltration in vivo. In agreement with this, during an acute DMN (100 mg/kg) exposure, cellular infiltration was almost completely absent in TNFR-1 KO mice, and was completely absent in TNFR DKO as compared to WT and TNFR-2 KO mice (Fig. 2B
). Importantly, our results also show that high-dose DMN-induced hepatotoxicity can occur in the absence of liver inflammation. TNFR-1 KO and TNFR DKO mice had similar necrosis scores to WT mice despite the paucity of inflammatory cell accumulation (Fig. 2
).
Recently, Peschon et al. (1998) observed decreased pulmonary neutrophil influx in TNFR-1 KO and TNFR DKO mice and exacerbated neutrophil accumulation in the lungs of TNFR-2 KO mice following Micropolyspora faeni infection. They concluded that TNFR-1 is responsible for neutrophil influx during bacterial-induced pulmonary inflammation and that TNFR-2 may be important for down-regulating the inflammatory response. These data further support our acute, high-dose DMN experiments in which TNFR-1 KO and TNFR DKO mice had little cellular infiltrates, while TNFR-2 KO mice had levels comparable to WT (Fig. 2B). Hepatotoxicity following an acute DMN (100-mg/kg) dose is significantly higher in TNFR-2 KO mice compared to WT, TNFR-1 KO, and TNFR DKO. Interestingly, TNFR-2 KO mice were apparently more susceptible to acute DMN (100 mg/kg)-induced lethality, since 37.5% were found dead prior to sacrifice. Because these dead TNFR-2 KO mice were not included in the scoring procedure, the level of necrosis presented in Figure 2A
may be underestimated. This further suggests that TNFR-2 signaling may be providing some protective responses because TNFR-1 KO mice had lower necrosis compared to TNFR-2 KO mice. Taken together, these data suggest that TNFR-1 delivers detrimental signals that may be counteracted by TNFR-2-mediated signals. It has not been determined whether TNFR-2-deficient mice reflect a down-regulated inflammatory response at cytokine transcript levels.
TNFR-deficient mice (same strains as used in our experiments) express 5-fold higher TNF protein following LPS exposure than do WT mice (Peschon et al., 1998
), and this may explain the elevated damage in TNFR-2 KO mice following DMN (100 mg/kg) (Fig. 2A
). Because TNFR-1 signaling is still intact in TNFR-2 KO mice, increased hepatic expression of TNF
following exposure to inflammatory mediators (LPS, DMN or CCl4) can act on TNFR-1 to initiate destructive responses. However, it cannot be ruled out that the differences we observed in necrosis scores may be due to signaling through TNFR-2 that provides protective responses to counteract TNFR-1-mediated damage.
Recent evidence indicates that high dose DMN exposure (100 mg/kg) induces an apoptotic mechanism that may contribute to toxicity (Ray et al., 1992). However the hepatic genes involved were not examined. We observed upregulation of Bax and Bcl-XL following acute, high-dose DMN or CCl4 exposure, supporting that regulation of these genes determines the fate of apoptosis, independent of TNF signaling.
Bfl-1 (also called A1) has been shown to suppress p53-induced apoptosis (D'Sa-Eipper et al., 1996). Previous reports showed that Bfl-1 induction in cultured endothelial cells is mediated by TNF
, and increased expression of Bfl-1 protects against TNF-mediated cell death (Karsan et al., 1996a
; 1996b
). Consistent with this, hepatic Bfl-1 gene expression was upregulated in a TNFR-dependent manner during CCl4 but not DMN exposure. High-dose DMN exposure slightly induced hepatic Bfl-1 expression compared to naive but not vehicle controls in WT mice (Table 1
). In contrast, corn oil controls did not upregulate Bfl-1 transcript levels, and Bfl-1 transcripts were greatly elevated in CCl4-treated livers from WT but not TNFR DKO mice (Fig. 7
and Table 2
). Thus, TNF
mediates CCl4-, but not DMN-induced hepatic expression of Bfl-1, and either TNFR can provide the necessary signals.
In summary, through the utilization of TNFR KO mice, we have shown that TNF is a key mediator in hepatic immunocyte infiltration in addition to regulating necrotic events during acute, high-dose chemical exposure. The outcome of hepatotoxicity and inflammation depends on specific TNFR signaling. Further, both the molecular response and the role of TNF
in regulating hepatic inflammatory cytokine, cytokine receptor, and apoptotic gene expression is unique for DMN and CCl4. Thus, it may be necessary to individually evaluate the contribution of TNF
to individual hepatotoxic processes for various xenobiotics.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Department of Veterinary PathoBiology, University of Minnesota, 295e Animal Science/Veterinary Medicine, 1988 Fitch Avenue, St. Paul, MN 55108. Fax: (612) 6250204. E-mail: ruthe003{at}tc.umn.edu.
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