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

Abstract

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...

Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation

“…Previously, APAP was found to activate JNK in (Latchoumycandane et al, 2007;Jaeschke et al, 2012a). Recently, studies in mice have suggested that JNK2 plays a crucial role in APAP-induced liver injury (Latchoumycandane et al, 2006;Gunawan and Kaplowitz, 2007;Bourdi et al, 2008). In the present study, JNK2 phosphorylation activated by APAP was greatly inhibited by AChEI treatment (Fig.…”

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

“…Although initial phosphorylation signals precede increased ALT levels, it is not yet clear from our data whether phosphorylation of JNK/ERK contributes to hepatotoxicity in Gstp1 WT mice or is reflective of the condition of the liver in response to APAP. Defining the role of JNK in APAP toxicity is complex, as deletion of individual JNK isoforms in mice has demonstrated inconsistent changes in APAP sensitivity (Gunawan et al, 2006;Bourdi et al, 2008). A number of studies have reported that GSTP can modulate the activity of JNK by binding through its C terminus (Wang et al, 2001), preventing phosphorylation of its downstream targets in response to stress (Castro-Caldas et al, 2012).…”

Pathophysiological significance of c-junN-terminal kinase in acetaminophen hepatotoxicity

“…This hypothesis has been supported by numerous studies using genetic or pharmacological intervention strategies. However, it has also been challenged by several findings, especially those from recent studies [32]. Therefore, the current review aims at addressing the conflicting findings from those studies exploring the role of JNK in APAP hepatotoxicity.…”

“…However, these findings were quickly challenged. Studies from several research groups failed to reproduce the protective effect in JNK2-deficient mice [26,30,32]. More surprisingly, one study even pointed out that JNK2 signaling may actually have a beneficial role in APAP hepatotoxicity, and JNK2-deficient mice had higher liver injury which may have been due to compromised tissue repair [32].…”