Background & aims
The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and
p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory
cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine
kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential
against hepatic I/R injury.
Methods
The effects of nilotinib on liver I/R injury were tested using a murine model of warm,
segmental liver I/R. Serum ALT was measured and livers were analyzed by histology,
RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation
and cytokine production were also tested.
Results
Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury
and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine
kinases. Nilotinib lowered intrahepatic expression of IL-1β, IL-6, MCP-1, and MIP-2
and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38
MAPK signaling and decreased the recruitment of inflammatory monocytes and their production
of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes
cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine
production by stimulated NPCs.
Conclusions
Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be
useful for ameliorating liver I/R injury in humans.
Abbreviations:
MAPK (mitogen-activated protein kinase), JNK (c-Jun-N-terminal kinase), I/R (ischemia/reperfusion), ALT (alanine aminotransferase), NPC (non-parenchymal cell), MAP2K (MAPK kinase), MAPKAPK2 (MAPK activating protein kinase 2), PDGFR (platelet-derived growth factor receptor), CSF-1R (colony stimulating factor receptor 1), WT (wild type), TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), TLR9 (Toll-like receptor 9)Keywords
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Article info
Publication history
Published online: May 28, 2012
Accepted:
May 19,
2012
Received in revised form:
May 15,
2012
Received:
January 30,
2012
Identification
Copyright
© 2012 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
