Hepatoprotective Role of Endogenous Interleukin-13 in a Murine Model of Acetaminophen-Induced Liver Disease

Yee, Steven B.; Bourdi, Mohammed; Masson, Mary Jane; Pohl, Lance R.

doi:10.1021/tx600349f

Cited by 62 publications

(73 citation statements)

References 64 publications

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“…[34][35][36] These observations would indicate the essential involvement of inflammatory responses in the development of liver damages caused by APAP. Accumulating evidence implicates IL-1a and IL-1b as crucial mediators in various inflammatory reaction 11,[13][14][15] and their endogenous antagonist, IL-1ra, can inhibit the biological activities of IL-1s by competitive binding to IL-1RI.…”

Section: Discussionmentioning

confidence: 87%

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

Ishibe

Kimura

Ishida

et al. 2009

Laboratory Investigation

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Acetaminophen (APAP) induced increases in intrahepatic expression of interleukin (IL)-1a, IL-1b, and IL-1 receptor antagonist (IL-1ra), when administered intraperitoneally. These observations prompted us to define the pathophysiological roles of IL-1ra in APAP-induced liver injury. Compared with wild-type (WT) mouse-derived hepatocytes, IL-1ra-deficient (IL-1ra KO)-derived hepatocytes exhibited more resistance against APAP but not APAP-derived major toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Moreover, the amounts of a major APAP adduct (selenium-binding protein), an indicator of NAPQI generation from APAP, was significantly lower in IL-1ra KO mice than WT mice with depressed intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, the enzymes crucially involved in NAPQI generation from APAP. These observations would indicate that IL-1ra deficiency impaired APAP metabolism. IL-1a and IL-1b were expressed to similar extents in livers of untreated IL-1ra KO and WT mice. By contrast, the intranuclear amount of p65 of NF-kB, which can suppress the gene expression of CYP1A2, CYP2E1, and CYP3A11, was higher in untreated IL-1ra KO than WT mice. Moreover, when mice were intraperitoneally administered APAP (200 mg/kg), IL-1ra KO mice exhibited attenuated APAP-induced liver injury as evidenced by reductions in serum alanine transferase levels and histopathological changes such as centrilobular necrosis, hemorrhages, and leukocyte infiltration. Finally, when given 12 h before APAP challenge, IL-1a repressed the intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, eventually reducing APAP-induced liver injury, along with reduction in APAP adducts. Collectively, NF-kB was activated without any stimuli by the genetic disruption of IL-1ra, and suppressed cytochrome P450 enzyme expression, thereby reducing APAP-induced liver injury.

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Section: Discussionmentioning

confidence: 87%

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

Ishibe

Kimura

Ishida

et al. 2009

Laboratory Investigation

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“…Quantitative evaluation of liver injury in H&E-stained sections was analyzed morphometrically by light microscopy using Axiovision software (v4.5; Carl Zeiss Microimaging, Inc., Thornwood, NY) and a 64-point grid [24]. Approximately 10% of the total area of each liver section was examined.…”

Section: Assessment Of Liver Injurymentioning

confidence: 99%

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

Bourdi

Korrapati²,

Chakraborty³

et al. 2008

Biochemical and Biophysical Research Communications

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Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI. When male C57BL/6J wild type (WT) and JNK2 −/− mice were treated with 300mg APAP/kg, 90% of JNK2 −/− mice died of ALF compared to 20% of WT mice within 48 h. The high susceptibility of JNK2 −/− mice to AILI appears to be due in part to deficiencies in hepatocyte proliferation and repair. Therefore, our findings are consistent with JNK2 signaling playing a protective role in AILI and further suggest that the use of JNK inhibitors as a potential treatment for AILI, as has been recommended by other investigators, should be reconsidered. KeywordsAcetaminophen; Cyclin D1; Hepatoprotection; c-Jun N-terminal kinase 2; JNK2; Liver injury; Proliferating cell nuclear antigen; Repair Overdose of APAP, a popular antipyretic and analgesic, is a leading cause of ALF resulting in approximately 1,800 deaths per year in the United States [1]. Although the initiating events in AILI have been attributed to reactive metabolite and protein adduct formation as well as glutathione depletion [2][3][4], the downstream signaling pathways controlling or promoting the severity of AILI have become of a great interest to many researchers [5][6][7][8][9][10][11][12][13][14]. One of these pathways involves JNK, which when activated is known to influence important cellular events, including alterations in gene expression [15], cell death [16], cellular proliferation and survival [17][18][19][20].Recent studies involving AILI in JNK2 −/− mice have led to conflicting results where JNK2 −/− mice were found to be either less susceptible [21] Animals and APAP treatmentSeven to 9 week-old male WT, JNK1 −/− and JNK2 −/− mice on a C57BL/6J background were purchased from Jackson Laboratories (Bar Harbor, ME). Mice were acclimated for at least 1 week to a 12-h light/dark cycle in a humidity and temperature-controlled, specific-pathogenfree environment in microisolator autoclaved cages. Mice were allowed autoclaved food and water ad libitum until experimental use. Before each study, mice were fasted overnight (14-16h; free access to water) to uniformly deplete hepatic GSH stores [23]. Food supplies were restored after intraperitoneal administration of APAP (300mg/kg in warm saline; 20ml/kg) or saline vehicle (20ml/kg). All maintenance of animals conformed to the guidelines for humane treatment set by the Association for Assessment and Accreditation for Laboratory Animal Care International's Guide for the Care and Use of Laboratory Animals and by the National Institutes of Health. Sera and tissue collectionBlood samples were collected and allowed to clot in microtainer serum separator tubes (Becton Dickinson and Co., Franklin Lakes, NJ) for approximately 2h at room temperature and then centrifuged. Serum was separated and used for ALT measurements. A por...

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“…Inflammatory mediators, including the cytokines TNF and IL-13, nitric oxide (NO), inducible NO synthase (iNOS), natural killer cells, and PMN, were shown to participate in the toxic effects of APAP, although the specific roles of some of these factors are not fully understood (Smith et al, 1998;Gardner et al, 2002Gardner et al, , 2003Ishida et al, 2004;Liu et al, 2004Liu et al, , 2006Yee et al, 2007). Results of studies presented here demonstrate that inflammatory stimuli likely to be associated with septicemia and viral hepatitis may increase sensitivity to APAP-induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…A protective role for IL-13 in APAP hepatotoxicity has been suggested. In IL-13 knockout mice, APAP-induced liver injury was more severe than in wild-type mice, and a number of inflammatory markers were upregulated to a greater degree (Yee et al, 2007). Several investigators presented evidence that NO contributes to APAP-induced liver damage (Hinson et al, 2004;Gardner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Bacterial- and Viral-Induced Inflammation Increases Sensitivity to Acetaminophen Hepatotoxicity

Maddox

Amuzie

et al. 2009

Journal of Toxicology and Environmental Health, Part A

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Acetaminophen (APAP)-induced hepatotoxicity accounts for nearly half of acute liver failure cases in the United States. The doses that produce hepatotoxicity vary considerably and many risk factors have been proposed, including liver inflammation from viral hepatitis. Interestingly, inflammatory stress from another stimulus, bacterial endotoxin (lipopolysaccharide, LPS), renders the liver more sensitive to hepatotoxicity from numerous xenobiotic agents. The purpose of these studies was to test the hypothesis that inflammation induced by LPS or infection with reovirus increases sensitivity to APAP-induced liver injury. For LPS-induced inflammation, C57BL/6J mice were treated with either saline or LPS (44 x 10(6) EU/kg, ip) 2 h before treatment with APAP (100-400 mg/kg, ip) or saline. No elevation in serum alanine aminotransferase (ALT) activity was observed in mice that received vehicle or LPS alone. LPS co-treatment produced a leftward shift of the dose-response curve for APAP-induced hepatotoxicity and led to significantly greater tumor necrosis factor-alpha (TNF) production than APAP alone. Reovirus serotype 1 (10(8) PFU, iv) induced inflammation in Balb/c mice as evidenced by increases in hepatic mRNAs for macrophage inhibitory protein-2, interleukin-6, and TNF. Co-administration of reovirus and APAP at doses of 450 and 700 mg/kg (2 h after reovirus) led to increases in serum ALT activity, whereas neither reovirus nor APAP alone produced liver injury. Consistent with the increases in serum ALT activity, histopathologic examination revealed centrilobular necrosis with marked neutrophilic accumulation only in livers of mice treated with LPS/APAP or with reovirus/APAP. The results suggest that normally noninjurious doses of APAP are rendered hepatotoxic by modest inflammation, whether bacterial or viral in origin.

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Hepatoprotective Role of Endogenous Interleukin-13 in a Murine Model of Acetaminophen-Induced Liver Disease

Cited by 62 publications

References 64 publications

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

Bacterial- and Viral-Induced Inflammation Increases Sensitivity to Acetaminophen Hepatotoxicity

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