SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

Lee, Kyung-Hoon; Kim, Sang Eun; Lee, Yong Kyu

doi:10.1038/emm.2006.48

Cited by 30 publications

(30 citation statements)

References 33 publications

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“…It was proposed that JNK had a pathological role in AILI in part by contributing to mitochondrial injury [14,21,35]. Potential limitations of these studies, as acknowledged by the investigators [21,22] is that JNK inhibitors may not be specific and as reported can affect other signaling events that could lead to the misinterpretation of results [36][37][38][39]. Further, some of the JNK inhibitors were dissolved in vehicles containing DMSO [14,21] and polyethylene glycol [22,35], which may affect various parameters at the cellular and molecular level [34,[40][41][42][43].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Although JNK activation has been associated with liver IRI, its role in liver cell death or tissue inflammation remains controversial. 30,31 The ability of IR to induce JNK activation in CXCL10 KO mice indicates that it associates rather with the triggering event, that is, the initial ischemia-induced hepatocellular injury than the pro-inflammatory response per se. Conversely, the suppression of ERK activation suggests its role in liver inflammation further downstream IR cascade, that is, the inflammation-induced hepatocellular damage.…”

Section: Discussionmentioning

confidence: 99%

CXCL10 regulates liver innate immune response against ischemia and reperfusion injury

et al. 2007

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We have shown that activation of toll-like receptor 4 (TLR4) and its interferon regulatory factor 3 (IRF3)-dependent downstream signaling pathway are required for the development of liver ischemia/reperfusion injury (IRI). This study focused on the role of TLR4-IRF3 activation pathway products, in particular, chemokine (C-X-C motif) ligand 10 (CXCL10). The induction of CXCL10 by liver IR was rapid (1 hour postreperfusion), restricted (ischemic lobes), and specific (no CXCL9 and CXCL11 induction). I schemia/reperfusion injury (IRI) develops in the absence of exogenous Ag, and innate immunity has been thought to play a dominant pathogenic role. [1][2][3] Liver ischemia activates Kupffer cells, and to a lesser degree endothelial cells as well as hepatocytes, leading to the formation of reactive oxygen species and secretion of proinflammatory cytokines/chemokines. The oxidant stress directly damages endothelial cells/hepatocytes, whereas the soluble factors are largely responsible for leukocyte recruitment and activation, leading to the full development of intrahepatic inflammation causing further organ damage. Although excessive pro-inflammatory response has been recognized as the key element leading to IRI, the mechanisms that initiate and regulate liver inflammation cascade remain to be elucidated.We and others have reported that mammalian sentinel receptor toll-like receptor 4 (TLR4) is involved in the initiation of IRI. [4][5][6][7] We found that livers in TLR4 knockout (KO) mice were protected from IRI and associated inflammation. 4-7 Furthermore, MyD88-independent signaling mediated by IRF3, downstream of TLR4 activation, was critical, because mice deficient in interferon regulatory factor 3 (IRF3) but not MyD88 were protected from IRI. 5 MyD88-dependent signaling in TLR4 activation pathway leads to direct nuclear factor kappa B activation and induction of pro-inflammatory cytokines, whereas the IRF3-mediated signaling induces type 1 IFN

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“…7A). This rapid activation of JNK in RPH and NRPH participated in the acceleration of the liver regenerative response since injection of SP600125 before surgical procedure, a reversible inhibitor of JNK activity commonly used in the literature [4,[23][24][25][26] 18 h after resection. This response was correlated with low levels of Cyclin D1 and p21 Cip1 expression, the latter usually exhibiting a biphasic induction in mid-G1 and S-phase [21] (Fig.…”

Section: Acceleration Of the Liver Response Is Related To C-jun N-termentioning

confidence: 98%

Reperfusion stress induced during intermittent selective clamping accelerates rat liver regeneration through JNK pathway

Duval

Mbatchi

Grandadam

et al. 2010

Journal of Hepatology

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SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

Cited by 30 publications

References 33 publications

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

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

CXCL10 regulates liver innate immune response against ischemia and reperfusion injury

Reperfusion stress induced during intermittent selective clamping accelerates rat liver regeneration through JNK pathway

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