Critical role of c-jun (NH2) terminal kinase in paracetamol-induced acute liver failure

Henderson, Neil C.; Pollock, Katharine J.; Frew, John; MacKinnon, Alison C.; Flavell, Richard A.; Davis, Roger J.; Sethi, Tariq; Simpson, Kenneth J.
July 2007
Gut;Jul2007, Vol. 56 Issue 7, p982
Academic Journal
Background: Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and is a key intracellular signalling molecule involved in controlling the fate of cells. Aim: To examine the role of JNK in paracetamol-induced acute liver failure (ALF). Methods: A previously developed mouse model of paracetamol poisoning was used to examine the role of JNK in paracetamol-induced ALF. Results: Paracetamol-induced hepatic JNK activation both in human and murine paracetamol hepatotoxicity and in our murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in routine paracetamol hepatotoxicity, with a significant reduction in hepatic necrosis and apoptosis. In addition, delayed administration of the JNK inhibitor was more effective than N-acetylcysteine after paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride-mediated or anti-Fas antibody-mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic tumour necrosis factor α (TNF α) production after paracetamol poisoning. Conclusions: These data demonstrated a central role far JNK in the pathogenesis of paracetamol-induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity.


Related Articles

  • Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling. Mittal, Nitish; Tan, Miao; Egbuta, Onyemachi; Desai, Nina; Crawford, Cynthia; Xie, Cui-Wei; Evans, Christopher; Walwyn, Wendy // Neuropsychopharmacology;Jul2012, Vol. 37 Issue 8, p1953 

    The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking β-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by β-arrestin 2 is cJun-N-terminal...

  • Apamin Attenuated Cerulein-Induced Acute Pancreatitis by Inhibition of JNK Pathway in Mice. Bae, Gi-Sang; Heo, Kwang-Ho; Park, Kyoung-Chel; Choi, Sun; Jo, Il-Joo; Seo, Seung-Hee; Kim, Dong-Goo; Shin, Joon-Yeon; Kang, Dae-Gil; Lee, Ho-Sub; Song, Ho-Joon; Shin, Byung-Cheul; Park, Sung-Joo // Digestive Diseases & Sciences;Oct2013, Vol. 58 Issue 10, p2908 

    Background/Aim: We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP....

  • Nuclear and cytosolic JNK signalling in neurons. Coffey, Eleanor T. // Nature Reviews Neuroscience;May2014, Vol. 15 Issue 5, p285 

    It has been over 20 years since JUN amino-terminal kinases (JNKs) were identified as protein kinases that are strongly activated by cellular stress and that have a key role in apoptosis. Examination of Jnk-knockout mice and characterization of JNK behaviour in neuronal cells has further revealed...

  • JNK Pathway Activation Is Controlled by Tao/TAOK3 to Modulate Ethanol Sensitivity. Kapfhamer, David; King, Ian; Mimi E. Zou; Lim, Jana P.; Heberlein, Ulrike; Wolf, Fred W. // PLoS ONE;Dec2012, Vol. 7 Issue 12, p1 

    Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. Here we demonstrate that JNK signaling functions downstream of the...

  • Inhibition of Spinal Interlukin-33/ST2 Signaling and Downstream ERK and JNK Pathways in Electroacupuncture Analgesia in Formalin Mice. Han, Ping; Liu, Shenbin; Zhang, Mengting; Zhao, Jing; Wang, Yanqing; Wu, Gencheng; Mi, Wenli // PLoS ONE;Jun2015, Vol. 10 Issue 6, p1 

    Although acupuncture is widely used to manage pain, it remains highly controversial, largely due to the lack of a clear mechanism for its benefits. Here, we investigated the role of IL-33, a novel interleukin (IL)-1 family member, and its receptor ST2 in the analgesic effects of...

  • Diverse Roles of JNK and MKK Pathways in the Brain. Yamasaki, Tokiwa; Kawasaki, Hiroshi; Nishina, Hiroshi // Journal of Signal Transduction;2012, p1 

    The c-Jun NH2-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 4 and MKK7, which are activated by various MAPKKKs. Studies employing knockout mice have...

  • Inhibition of c-Jun N-Terminal Kinase Attenuates Low Shear Stress-Induced Atherogenesis in Apolipoprotein E-Deficient Mice. Juan Wang; Feng Shuang An; Wei Zhang; Lei Gong; Shu Jian Wei; Wei Dong Qin; Xu Ping Wang; Yu Xia Zhao; Yun Zhang; Cheng Zhang; Ming-Xiang Zhang // Molecular Medicine;Sep/Oct2011, Vol. 17 Issue 9/10, p990 

    Atherosclerosis begins as local inflammation of arterial walls at sites of disturbed flow, such as vessel curvatures and bifurcations with low shear stress. c-Jun NH2-terminal kinase (JNK) is a major regulator of flow-dependent gene expression in endothelial cells in atherosclerosis. However,...

  • Activin B Promotes Epithelial Wound Healing In Vivo through RhoA-JNK Signaling Pathway. Min Zhang; Nu-Yun Liu; Xue-Er Wang; Ying-Hua Chen; Qing-Lin Li; Kang-Rong Lu; Li Sun; Qin Jia; Lu Zhang; Lin Zhang // PLoS ONE;2011, Vol. 6 Issue 9, p1 

    Background: Activin B has been reported to promote the proliferation and migration of keratinocytes in vitro via the RhoAJNK signaling pathway, whereas its in vivo role and mechanism in wound healing process has not yet been elucidated. Principal Findings: In this study, we explored the...

  • Targeting JNK by a New Curcumin Analog to Inhibit NF-kB-Mediated Expression of Cell Adhesion Molecules Attenuates Renal Macrophage Infiltration and Injury in Diabetic Mice. Pan, Yong; Zhang, Xiuhua; Wang, Yi; Cai, Lu; Ren, Luqing; Tang, Longguang; Wang, Jingying; Zhao, Yunjie; Wang, Yonggang; Liu, Quan; Li, Xiaokun; Liang, Guang // PLoS ONE;Nov2013, Vol. 8 Issue 11, p1 

    Macrophage infiltration contributes to the pathogenesis of diabetic renal injury. However, the regulatory mechanisms between macrophage infiltration and epithelial cell activation are still unclear. Our previous study found that C66, a novel curcumin analog, was able to inhibit inflammatory...


Read the Article


Sign out of this library

Other Topics