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in the pathogenesis of acetaminophen-induced acute liver injury
Division of Environmental Sciences, Forensic and Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan;
* Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan;
Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
1Correspondence: Division of Environmental Science, Forensic and Social Environmental Medicine, Graduate School of Medical Science, Kanazawa University, 13–1 Takara-machi, Kanazawa 920-8640, Ishikawa, Japan. E-mail: ohshimat{at}med.kanazawa-u.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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mRNA expression and a marked increase in serum transaminase levels, leading to acute lethality of 
45%. Histopathological examination showed centrilobular hepatic necrosis with leukocyte infiltration and a large number of apoptotic hepatocytes 10 and 24 h after APAP challenge. mRNA expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin (IL) 1
, IL-1ß, IL-6, tumor necrosis factor , monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP) 1, MIP-2, KC, IP-10, Mig, Fas, and inducible nitric oxide synthase was enhanced in the liver of wild-type mice injected with APAP. To clarify the role of IFN- in this process, IFN--deficient mice were treated in the same manner. All IFN--deficient mice survived with reduced serum transaminase elevation and attenuated hepatic necrosis, leukocyte infiltration, and hepatocyte apoptosis. The gene expression of all molecules was significantly attenuated in IFN--deficient mice. Administration of an anti-IFN- neutralizing antibody even 2 or 8 h after APAP challenge to wild-type mice alleviated APAP-induced liver injury, and all mice survived. Thus, IFN- is responsible for APAP-induced liver injury by mediating leukocyte infiltration, hepatocyte apoptosis, and NO production as well as cytokine and chemokine production. Moreover, immunoneutralization of IFN- may be therapeutically effective for developing APAP-induced liver injury.—Ishida, Y., Kondo, T., Ohshima, T., Fujiwara, H., Iwakura, Y., Mukaida, N. A pivotal involvement of IFN- in the pathogenesis of acetaminophen-induced acute liver injury.
Key Words: interferon • chemokines • adhesion molecules • nitric oxide synthase
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. It is generally accepted that the toxicity of APAP is mediated by cytochrome P450 to generate a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by glutathione (GSH) in the liver (3)
. However, overdose of APAP depletes hepatic GSH and NAPQI covalently binds to cysteine residues on proteins, resulting in the formation of 3-(cysteine-S-yl) APAP adducts (4)
. N-Acetyl-cysteine (NAC), a precursor of GSH, is a standard therapeutic regimen for APAP overdose cases with acute liver injury and fulminant hepatitis (5)
. Because the symptoms of APAP overdose may frequently be overlooked, however, the NAC treatment is often ineffective for APAP toxicity due to its short therapeutic window (6)
.
Cytokines and chemokines are presumed to be crucially involved in the development of acute liver injury by APAP. Blazka et al. (7
, 8)
suggested that tumor necrosis factor (TNF-) and interleukin 1 (IL-1) were released in APAP intoxication and responsible for pathological manifestations of APAP-induced liver injury. However, the pathophysiological roles of TNF- remain unclear, because suppression of TNF- expression was ineffective in diminishing APAP-induced liver injury (9)
and there was no difference in the severity of APAP-induced liver injury between TNF-/lymphotoxin double knockout and control mice (10)
. Chemokines such as macrophage inflammatory protein 2 (MIP-2) and KC, which are chemotactic factors for neutrophils, were released from hepatocytes exposed to acetaminophen in vitro (11)
. In vivo MIP-2 gene transfer using an adenovirus vector or exogenous MIP-2 administration diminished APAP-induced liver injury (12
, 13)
. Moreover, Hogaboam et al. (14)
demonstrated that APAP-induced liver injury was exaggerated in mice deficient in C-C chemokine receptor 2 (CCR2), a receptor specific for monocyte chemoattractant protein 1 (MCP-1), and they claimed that the MCP-1 signals through CCR2 expressed in the liver provided a hepatoprotective effect in its regulation of cytokine production during APAP challenge (14)
. Thus, these observations suggest that several chemokines have protective roles against APAP-induced liver injury.
Though aberrant IFN- production has been documented in viral hepatitis and experimental liver injury models (15
16
17)
, the biological role of IFN- in APAP-induced liver injury has not been examined in detail. There were clinical observations that administration of APAP to patients undergoing IFN therapy unexpectedly caused a significant elevation in serum hepatic transaminase levels, suggesting synergic effects of APAP and IFN on acute liver injury (18)
. Hence, we examined the roles of IFN- in acute liver injury by APAP using IFN--deficient (IFN--/-) mice. We demonstrated that IFN--/- mice exhibited attenuated APAP-induced liver injury along with reduced leukocyte infiltration and diminished gene expression of inflammatory cytokines, chemokines, adhesion molecules, Fas, and inducible nitric oxide synthase (iNOS) compared with wild-type (WT) mice. Finally, we provide definitive evidence that the administration of anti-IFN- antibody even at 2 or 8 h after APAP challenge attenuated APAP-induced liver injury, thus implying that immunoneutralization of IFN- is therapeutically effective in treatment of developing APAP-induced liver injury.
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MATERIALS AND METHODS |
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Mice
Pathogen-free 8-wk-old male BALB/c mice were obtained from Sankyo Laboratories (Tokyo, Japan) and designated as WT mice in the present experiments. To generate IFN--/- mice, animals heterozygous for a germ-line null mutation of the IFN- gene were backcrossed to BALB/c mice for at least six generations (19)
. Homozygous mice were further inbred to generate sufficient numbers of mice for the experiments as described and designated as IFN--/- mice. Eight-week-old male IFN--/- mice were used for experiments compiled with the standards set out in the Guidelines for the Care and Use of Laboratory Animals at the Takara-machi Campus of Kanazawa University and housed individually in cages under specific pathogen-free conditions during the course of the experiments.
APAP-induced liver injury
Fresh suspensions of APAP were made by dissolving the compound in phosphate-buffered saline (PBS, pH 7.2) warmed to 37°C immediately before each experiment. In all experiments, mice were allowed access to water alone for 10 h, then were i.p. injected with APAP at a concentration of 750 mg/kg. In some experiments, PTIO (50 mg/kg) (20)
, L-NAME (50 mg/kg) (21)
, or anti-IFN- mAb (250 µg) (19)
was administered to the animals at 2 or 8 h after APAP challenge. Doses were determined as those minimally required in our preliminary experiments (data not shown).
Determination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels
At 2, 6, 10, 24, and 48 h after APAP challenge, the serum levels of AST and ALT were determined with a Fuji DRI-CHEM 5500V (Fuji Medical System, Tokyo, Japan).
Histopathological and immunohistochemical analyses
The mice were killed 10 and 24 h after APAP challenge and liver specimens were obtained. The liver specimens were fixed in 4% formaldehyde buffered with PBS (pH 7.2), followed by making paraffin-embedded sections (6 µm thick). Thereafter, hematoxylin and eosin staining or immunostaining using anti-MPO Ab for neutrophils, anti-F4/80 Ab for macrophages, anti-CD3 Ab for T cells, or anti-ssDNA Ab for apoptotic hepatocytes (22)
. In the immunostained sections, the numbers of neutrophils, macrophages, and T cells in the liver and apoptotic hepatocytes were enumerated in 10 randomly chosen visual fields (magnification, x400) of the sections, and the average of 10 selected microscopic fields was calculated.
Extraction of total RNAs and RT-PCR
Total RNAs were extracted from liver samples using ISOGENE (Nippon Gene, Toyama, Japan). Five micrograms of total RNA was reverse-transcribed at 42°C for 1 h in 20 µL reaction mixture containing mouse Moloney leukemia virus reverse transcriptase (Toyobo, Osaka, Japan) with oligo (dT) primers (Amersham-Pharmacia Biotech Japan, Tokyo, Japan), followed by PCR amplification. Thereafter, cDNA was amplified together with Taq polymerase (Nippon Gene) using specific primers with an optimal number of cycles at 94°C for 1 min, optimal annealing temperature for 1 min, and 72°C for 1 min, followed by incubation at 72°C for 3 min (Table 1)
. The PCR products were fractionated on a 2% agarose gel and visualized by ethidium bromide staining. The band intensity of ethidium bromide fluorescence was measured using NIH Image Analysis Software Ver 1.61 (National Institutes of Health, Bethesda, MD). The intensities of the bands were determined with the use of the ratios to ß-actin.
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Statistical analysis
The means and SEs were calculated for all parameters determined in this study. Statistical significance was evaluated using analysis of variance or Mann-Whitney’s U test. P < 0.05 was accepted as statistically significant. The survival curve by the Kaplan-Meier procedure was analyzed by a log-rank test.
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RESULTS |
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gene expression in the liver of WT mice after APAP challenge was faintly detected in normal liver tissues of WT mice under the experimental conditions used, whereas IFN- mRNA expression was markedly increased 10 h after APAP challenge and returned to a basal level by 24 h (Fig. 1
a, b).
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Lethality and liver injury due to APAP administration
There was no significant difference in serum ALT and AST levels between WT and IFN--/- mice before APAP challenge (ALT: 35.3±7.9 IU/L vs. 21.5±3.9 IU/L; AST: 69.0±9.2 IU/L vs. 86.7±19.4 IU/L). After APAP challenge, 45% of WT mice (12 deaths/27 mice) succumbed to acute liver injury within 24 h whereas all IFN--/- mice (n=20 mice) survived until 48 h (Fig. 2
a). In WT and IFN--/- mice, serum ALT and AST levels began to increase at 6 and 10 h, respectively. Thereafter, both levels peaked at 24 h and decreased by 48 h after APAP challenge. However, the elevations in the serum ALT and AST levels were significantly attenuated in IFN--/- mice compared with WT mice (Fig. 2b, c
).
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Histologically, no apparent difference was observed in the liver specimens of untreated WT and IFN--/- mice (Fig. 2d, g
). Ten hours after APAP challenge, severe hemorrhages and centrilobular hepatic necrosis with concomitant leukocyte infiltration were observed in WT mice, and the liver injury was still evident at 24 h after APAP challenge (Fig. 2e, f
). However, the histopathological changes such as hemorrhage and centrilobular hepatic necrosis were minimally detectable in IFN--/- mice (Fig. 2h, i
), which may result in the elevation of serum ALT and AST levels. These observations demonstrate that hepatotoxicity of APAP was markedly attenuated in IFN--/- mice vs. WT mice.
Leukocyte infiltration in the liver
Before APAP challenge, there was no significant difference in the number of leukocytes such as neutrophils, macrophages, and T cells between WT and IFN--/- mice. In WT mice, neutrophil infiltration was observed 10 h after APAP challenge and peaked by 24 h (Fig. 3
a). Moreover, the number of macrophages and T cells peaked 10 h after APAP challenge (Fig. 3b, c
). Although leukocytes such as neutrophils (Fig. 3d
), macrophages (Fig. 3e
), and T cells (Fig. 3f
) were recruited in the liver of IFN--/- mice after APAP challenge, the number of every cell type was significantly reduced at 10 and 24 h after APAP challenge compared with WT mice (Fig. 3g-i
). These results suggested that in the absence of IFN-, leukocyte infiltration in the liver was reduced after APAP challenge.
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Apoptosis of hepatocytes due to APAP administration
Before APAP challenge, few apoptotic hepatocytes were observed in WT or IFN--/- mice. At 10 and 24 h after APAP challenge, a large number of apoptotic hepatocytes were observed in wild-type mice, whereas the number of apoptotic hepatocytes was significantly reduced in IFN--/- mice (Fig. 4
a–c). Thus, these results indicated that the absence of IFN- made hepatocytes more resistant to apoptotic signals induced by APAP.
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Gene expression of adhesion molecules, cytokines, chemokines, iNOS, Fas and Fas ligand (Fas-L) in the liver after APAP challenge
There was no significant difference in mRNA expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-1, IL-1ß, IL-6, TNF-, MCP-1, MIP-1, MIP-2, KC, Mig, and iNOS between untreated WT and IFN--/- mice under the conditions used (Fig. 5
a and Fig. 6
a). In contrast, IP-10 could be detected in the liver of untreated WT but not IFN--/- mice (Fig. 5a
). In WT mice, gene expression of all these molecules was enhanced in liver tissue after APAP challenge (Fig. 5b-i
). In IFN--/- mice, the enhanced gene expressions of those adhesion molecules, cytokines, and chemokines except for IP-10 were significantly attenuated at 10 and/or 24 h after APAP challenge when compared with WT mice, and IP-10 was never detected in IFN--/- mice (Fig. 5a
). These results suggested that the absence of IFN- reduced expression of these adhesion molecules, cytokines, and chemokines, and leukocyte infiltration. Similarly, the gene expression of iNOS was enhanced in WT mice after APAP challenge, but the gene expression of iNOS was not increased significantly in IFN--/- mice. These observations implied that iNOS was involved in liver injury induced by APAP (Fig. 6)
. Subsequently, we examined the gene expression of Fas and Fas-L in the liver. There was no significant difference in mRNA expression of Fas and Fas-L between WT and IFN--/- mice before APAP challenge (Fig. 4d
). APAP challenge enhanced gene expression of Fas in the liver of WT mice, whereas IFN--/- mice exhibited significantly reduced Fas mRNA expression compared with WT mice (Fig. 4e
). However, Fas-L gene expression was not enhanced in either WT or IFN--/- mice (Fig. 4f
). These observations suggested that the absence of IFN- likely reduced the expression of Fas but not Fas-L, resulting in the prevention of hepatocyte apoptosis.
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Effect of NO scavenger or NOS inhibitor
To clarify the role of NO in APAP-induced liver injury, WT mice were treated with L-NAME (NOS inhibitor) or PTIO (NO scavenger) 8 h after APAP challenge. Seven of 13 mice in the control group died from acute liver failure, but no death was observed in mice treated with L-NAME (n=10 mice) or PTIO (n=10 mice). Compared with mice treated with vehicle (PBS, pH 7.2), serum levels of AST and ALT in mice that survived were significantly reduced in mice treated with L-NAME or PTIO 24 h after APAP challenge (ALT: control; 8257±1725 IU/L, L-NAME; 965±317 IU/L P<0.05, PTIO; 122±37 IU/L P<0.01; AST: control; 3700±686 IU/L, L-NAME; 1620±981 IU/L P<0.05, PTIO; 598±300 IU/L P<0.05). These observations suggested that iNOS and NO contributed to the development of liver injury caused by APAP administration.
Effect of anti-IFN- antibody
We evaluated the therapeutic effects of anti-IFN- antibody on established APAP-induced liver injury. Based on the results of ALT and AST elevation in WT mice injected with APAP (Fig. 2b, c
), we administered anti-IFN- antibody to mice 2 or 8 h after APAP challenge. When administered with normal rat IgG 2 or 8 h after APAP challenge, several of the mice died (5 deaths/12 mice at 2 h; 6 deaths/12 mice at 8 h). In contrast, when mice were administered anti-IFN- antibody at 2 or 8 h, all mice survived (0 death/10 mice at 2 h; 0 death/10 mice at 8 h). Moreover, both ALT and AST levels were significantly reduced in mice treated with anti-IFN- antibody 2 h after APAP challenge compared with controls (Fig. 7
). Administration of anti-IFN- antibody even at 8 h decreased serum ALT and AST levels without statistical significance. These observations demonstrated that immunoneutralization of IFN- was therapeutically effective for the alleviation and acute lethality of APAP-induced liver injury.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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exerts pleiotropic effects including antiviral and bactericidal activities, activation of macrophages and NK cells, and up-regulation of MHC class II expression on macrophages. It is produced mainly by NK cells and Th1 cells (23)
and has been reported to be involved in various kinds of liver injury models (15
16
17)
. Enhanced IFN- expression is presumed to induce inflammatory responses, leading to parenchymal cell damage in the liver. In the present study, we observed that gene expression of IFN- was enhanced in the livers of mice treated with APAP. In APAP-induced liver injury, IFN- levels in the liver were correlated with severity. Clinically, APAP hepatotoxicity was markedly enhanced in patients treated with IFN (18)
. However, the precise molecular mechanism of APAP-induced liver toxicity has not been elucidated, particularly the roles of IFN-. Hence, we analyzed the pathological changes in IFN--/- mice treated with APAP.
The inflammatory process contributes to the development of liver injury induced by chemicals like APAP (24)
. In the inflammatory response, leukocytes such as neutrophils and macrophages are recruited to the injured organs. Administration of anti-neutrophil serum diminished ALT elevation in the serum and histological change of the liver in rats treated with APAP (25)
. Moreover, inactivation of macrophages markedly attenuated APAP-induced liver injury (26
, 27)
. Consistent with these previous studies, IFN--/- mice were resistant to APAP-induced liver injury with a concomitant reduction in leukocyte infiltration.
We previously observed that LPS treatment induced significantly less mononuclear cell infiltration in Propionibacterium acnes-primed IFN--/- mice compared with WT mice (19)
. Thus, IFN- may be involved in leukocyte infiltration into the inflamed liver. Accumulating evidence suggests that IFN- up-regulates ICAM-1 expression (23)
. In fact, the gene expression of adhesion molecules VCAM-1 and ICAM-1 was significantly reduced in IFN--/- mice treated with APAP compared with WT mice. Moreover, IFN--/- mice exhibited an attenuated expression of IL-1 and TNF-, both of which can up-regulate expression of these adhesion molecules (28
, 29)
. Thus, the absence of IFN- can suppress the expression of adhesion molecules directly and/or indirectly by reducing IL-1 and TNF- expression. IFN- in combination with IL-1ß or TNF- up-regulates MCP-1 in the mesothelial cells during peritoneal inflammation (30)
. In IFN--/- mice, the gene expressions of chemokines such as MCP-1, MIP-1, MIP-2, KC, Mig, and IP-10 were reduced compared with WT mice. Thus, reduction in chemokine expression further diminishes inflammatory cell infiltration in conjunction with reduced expression of adhesion molecules.
Several lines of evidence revealed the contribution of cytokines to APAP-induced acute liver injury. TNF- and IL-1 were released in response to APAP intoxication and were responsible for pathological manifestations of APAP-induced liver injury (7
, 8)
. Both of these cytokines can be produced by macrophages activated with IFN- (23)
. Thus, IFN- deficiency may reduce IL-1 and TNF- expression in the liver, as observed in the present model. Reduced expression of IL-1 and TNF- may attenuate liver injury directly in addition to the effects on adhesion molecules and chemokines. Several lines of evidence demonstrated that two chemokines, MIP-2 and MCP-1, have direct cytoprotective effects for APAP-induced acute liver injury (12
13
14)
. However, IFN--/- mice exhibited less severe APAP-induced liver injury despite a reduced expression of MIP-2 and MCP-1 compared with WT mice. Moreover, the present study demonstrated that the administration of anti-IFN- antibody 2 or 8 h after APAP challenge significantly attenuated APAP-induced liver injury. These observations suggest that IFN- may be involved directly in APAP-induced liver injury in addition to regulation of chemokine and adhesion molecule gene expression and subsequent inflammatory cell infiltration. NO is one of the factors causing liver injury, particularly concanavalin A-induced hepatitis (31)
. Controversies remain as to the roles of NO in APAP-induced liver injury: the inhibition of cytokine-mediated NO production potentiated APAP hepatotoxicity in vitro (32)
. However, the results from animal experiments provided evidence that NO contributes to APAP hepatotoxicity (33)
. Nakae et al. (34)
demonstrated that liposome-encapsulated superoxide dismutase prevented liver necrosis by APAP, suggesting the involvement of reactive oxygen (including NO) in APAP-induced liver injury. Here, we observed that iNOS gene expression was up-regulated in WT mice after APAP challenge whereas IFN--/- mice exhibited an attenuated expression of iNOS mRNA. Treatment with NO scavenger or NOS inhibitor markedly reduced APAP-induced liver injury in WT mice. Since IFN- can enhance iNOS expression in a variety of cells, including liver macrophages (31
, 35
, 36)
, the absence of IFN- may attenuate APAP hepatotoxicity by suppressing iNOS expression and subsequent NO production.
APAP not only induces centrilobular hepatic necrosis but also promotes hepatocyte apoptosis (37)
. Recent studies have demonstrated that the apoptosis of hepatocytes contributes to the overall hepatic injury associated with APAP toxicity (38)
. After APAP challenge, there was a large number of apoptotic hepatocytes around central veins with enhanced Fas mRNA expression in WT mice. In contrast, hepatocyte apoptosis was scarcely observed in IFN--/- mice, with concomitantly reduced Fas mRNA expression. Similarly, the degree of concanavalin A-induced hepatitis was attenuated significantly in IFN--/- mice along with reduced hepatocyte apoptosis, suggesting that IFN- plays a central role in concanavalin A-induced hepatitis by activating Fas-induced apoptosis of hepatocytes (17)
. Thus, IFN- may regulate hepatocyte apoptosis by modulating Fas expression in various types of liver injury, including the present model.
The results obtained from the present study demonstrate the crucial role of IFN- in the establishment of APAP-induced liver injury. However, we cannot exclude the possibility that additional factors have roles in the pathogenesis of APAP-induced liver injury, because IFN--/- mice exhibited discernible pathological changes in liver as well as increased serum levels of ALT and AST. Considering the previous studies, a number of factors, including leukocyte infiltration, inflammatory cytokines, Fas-induced apoptosis, and NO, are probably responsible for the hepatotoxic mechanisms of APAP (7
, 8
, 25
26
27
, 33
, 37
, 38)
. After APAP administration, IFN- up-regulates the expression of adhesion molecules and chemokines, resulting in leukocyte accumulation. Subsequently, recruited leukocytes produce inflammatory cytokines and chemokines that exacerbate the inflammatory responses in the liver. Concomitantly, IFN- induces iNOS expression and promotes hepatocyte apoptosis by up-regulating Fas expression. The synergy between these effects is presumed to cause liver injury. Thus, IFN- is centrally involved in the regulation of all these steps that are crucial for pathogenesis of APAP-induced liver injury. Alternatively, IFN- is a candidate target molecule in the therapeutic regimen of APAP-induced liver injury. In a previous study, pretreatment with anti-IFN- antibody at 2 h before APAP challenge prevented APAP-induced liver injury in CCR2 (a receptor for MCP-1) -deficient mice (14)
. However, it remains unclear whether the administration of anti-IFN- antibody even after APAP challenge can be effective to treat developing APAP-induced liver injury. The present study provides definitive evidence that the immunoneutralization of IFN- was therapeutically effective in attenuating acute lethality in APAP-induced liver injury, even when administered 8 h after APAP challenge. Therefore, IFN- is probably a good molecular target for the treatment of APAP-induced fatal liver injury.
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ACKNOWLEDGMENTS |
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Received for publication January 17, 2002.
Revision received March 22, 2002.
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 Y. Ito, E. R. Abril, N. W. Bethea, and R. S. McCuskey Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G60 - G67. [Abstract] [Full Text] [PDF]
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Z.-Q. Lin, T. Kondo, Y. Ishida, T. Takayasu, and N. Mukaida Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice J. Leukoc. Biol., June 1, 2003; 73(6): 713 - 721. [Abstract] [Full Text] [PDF]
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