Activation of c‐Jun N‐terminal kinase during ischemia and reperfusion in mouse liver

Onishi, Ichiro; Tani, Takashi; Hashimoto, Takeji; Shimizu, Kouichi; Yagi, Minoru; Yamamoto, Ken; Yoshioka, Katsuji

doi:10.1016/s0014-5793(97)01517-2

Cited by 31 publications

(21 citation statements)

References 28 publications

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“…In contrast, there are reports showing that JNK may stimulate necrosis or apoptosis of hepatocytes (50,51). Together these results indicate that JNK is involved in determining the balance between proliferation and apoptosis/necrosis of hepatocytes.…”

Section: Discussionmentioning

confidence: 72%

Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure

Streetz

Fregien

Plümpe

et al. 2001

The Journal of Immunology

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Con A administration results in dose-dependent immune-mediated liver injury. Cytokines are important to determine the outcome of liver failure in this model, and especially TNF-α and IFN-γ directly contribute to hepatocyte damage. The intracellular pathways of these two cytokines, which eventually result in tissue destruction, are not well defined. Here we used anti-IFN-γ Abs and adenoviral vectors that express molecules inhibiting distinct TNF-α-dependent pathways in hepatocytes to better understand the relevance of specific intracellular signaling cascades for Con A-induced liver failure. We show that activation of TNF-α- and IFN-γ-dependent intracellular pathways occurs prior to the influx of immune-activated cells into the liver and that anti-TNF-α and anti-IFN-γ neutralizing Abs cannot block infiltration of these cells. Blocking experiments with Abs and adenoviral vectors showed that NF-κB activation and the Fas-associated death domain protein/caspase 8 cascade in hepatocytes during Con A-induced liver failure have no impact on tissue injury. Additionally, STAT1 activation alone after Con A injection in liver cells does not result in liver damage. In contrast, IFN-γ-dependent expression of IFN regulatory factor-1 and TNF-α-dependent activation of c-Jun N-terminal kinase in liver cells correlates with liver cell damage after Con A injection. Therefore, our experiments indicate that IFN regulatory factor-1 and the c-Jun N-terminal kinase pathway are involved in determining hepatocyte damage during Con A-induced liver failure and thus may provide new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 72%

Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure

Streetz

Fregien

Plümpe

et al. 2001

The Journal of Immunology

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“…Several intracellular signaling pathways, including NF-B (Fan et al, 2004), p38 MAPK (Kobayashi et al, 2002), and JNK (Bradham et al, 1997;Onishi et al, 1997) are activated in hepatic I/R injury. The activation of signaling pathways is believed to evoke complicated inflammatory processes and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…c-Jun N-terminal kinase (JNK) is one of the signaling molecules activated in hepatic I/R injury (Onishi et al, 1997;Zwacka et al, 1998). JNK is activated by environmental stresses such as oxidative stress (Mendelson et al, 1996), and also by cytokines, including TNF- (Liedtke et al, 2002) and IL-1 (Finch et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Kim²,

Lee³

2006

Exp Mol Med

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Abstractc-Jun N-terminal kinase (JNK) is activated during hepatic reperfusion, and JNK inhibitors are known to protect other major organs from ischemia-reperfusion (I/R) injury. We attempted to determine the effect of SP600125, a JNK inhibitor, on hepatic I/R injury using a partial ischemia model in mice. Compared to a vehicle-treated group, the SP600125-treated group showed a greater increase in serum ALT levels 24 h after reperfusion with more severe parenchymal destruction and leukocyte infiltration. Similarly, tissue myeloperoxidase and malondialdehyde levels were higher in the SP600125-treated group, and chemokine expression was also higher in the SP600125-treated group. These data, which are contradictory to previous results, indicate that JNK inhibition by SP600125 may be harmful in hepatic I/R injury. Therefore, care must be taken when investigating the therapeutic use of JNK inhibitors in hepatic I/R injury, especially in the context of the effects of JNK inhibition on inflammatory infiltration.

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“…Protein Binding and Kinase Assays-Protein binding assays in COS-7 cells in vitro and immune-complex kinase assays were performed as described previously (14,16). P19 EC cells were lysed at 4°C in buffer (50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 5% glycerol, 3 mM MgCl 2 , 0.5% Nonidet P-40, 0.3 mM dithiothreitol) and precipitated with an anti-Raf-1 monoclonal antibody or anti-JSAP1 antiserum immobilized on Sepharose-coupled protein G (Life Technologies, Inc.).…”

Section: Methodsmentioning

confidence: 99%

A Scaffold Protein in the c-Jun NH2-terminal Kinase Signaling Pathways Suppresses the Extracellular Signal-regulated Kinase Signaling Pathways

Kuboki¹,

Ito²,

Takamatsu³

et al. 2000

Journal of Biological Chemistry

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We previously reported that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) functions as a putative scaffold factor in the JNK mitogen-activated protein kinase (MAPK) cascades. In that study we also found MEK1 and Raf-1, which are involved in the extracellular signal-regulated kinase (ERK) MAPK cascades, bind to JSAP1. Here we have defined the regions of JSAP1 responsible for the interactions with MEK1 and Raf-1. Both of the binding regions were mapped to the COOH-terminal region (residues 1054 -1305) of JSAP1. We next examined the effect of overexpressing JSAP1 on the activation of ERK by phorbol 12-myristate 13-acetate in transfected COS-7 cells and found that JSAP1 inhibits ERK's activation and that the COOH-terminal region of JSAP1 was required for the inhibition. Finally, we investigated the molecular mechanism of JSAP1's inhibitory function and showed that JSAP1 prevents MEK1 phosphorylation and activation by Raf-1, resulting in the suppression of the activation of ERK. Taken together, these results suggest that JSAP1 is involved both in the JNK cascades, as a scaffolding factor, and the ERK cascades, as a suppressor. The MAP kinase (MAPK)1 signaling pathway is an intracellular cascade consisting of MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). Upon stimulation, MAPKKK activates MAPKK by phosphorylation on serine (and/or threonine) residues, which in turn activates MAPK by phosphorylation on threonine and tyrosine residues (1, 2). A variety of MAPK cascades have been identified in organisms from yeast to mammals (3)(4)(5). In mammals, five groups of distinguishable MAPK cascades have been identified so far (6). They include the c-Jun NH 2 -terminal kinase (JNK) (also known as stressactivated protein kinase (SAPK), p38, and extracellular signalregulated kinase (ERK) cascades. The JNK and p38 groups of MAPKs are strongly activated in response to proinflammatory cytokines and environmental stresses (7-10). The ERK group of MAPKs is mostly responsive to mitogenic and differentiation stimuli (2,8). For example, the small G protein Ras is activated by many growth factors, and in turn activates the Raf-MEK-ERK cascades (11). The mammalian MAPK cascades play key roles in a wide array of cellular processes, including proliferation, differentiation, and apoptosis (7-11). Thus, mechanisms should exist to ensure specific and efficient activation of the MAPK cascades in response to extracellular stimuli. The recent identification of putative scaffold proteins in the MAPK cascades could account for one of the mechanisms (6,(12)(13)(14)(15). We proposed previously that JNK/SAPK-associated protein 1 (JSAP1) (also known as JNK-interacting protein 3 (15)) functions as a scaffold factor in the JNK MAPK cascades (14). In the same study, we reported that JSAP1 binds Raf-1 MAPKKK and MEK1 MAPKK, which are involved in the ERK MAPK cascades. Here, we have mapped the MEK1-and Raf-1-binding regions in JSAP1 and examined the effect of JSAP1 on the activation of the ERK MAPK casc...

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Activation of c‐Jun N‐terminal kinase during ischemia and reperfusion in mouse liver

Cited by 31 publications

References 28 publications

Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure

Dissection of the Intracellular Pathways in Hepatocytes Suggests a Role for Jun Kinase and IFN Regulatory Factor-1 in Con A-Induced Liver Failure

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

A Scaffold Protein in the c-Jun NH2-terminal Kinase Signaling Pathways Suppresses the Extracellular Signal-regulated Kinase Signaling Pathways

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