Basic—Liver, Pancreas, and Biliary TractModulation of Hepatic Fibrosis by c-Jun-N-Terminal Kinase Inhibition
Section snippets
Mice and Fibrosis Induction
Balb/c mice, JNK1-deficient mice (backcrossed 5 times to C57Bl/6 [http://jaxmice.jax.org/strain/004319.html]) and JNK2-deficient mice (in pure C57Bl/6 background [http://jaxmice.jax.org/strain/004321.html]), and C57Bl/6 mice were obtained from Jackson Laboratories (Bar Harbor, ME). JNK1-deficient mice were crossed with C57Bl/6 mice, and the resulting heterozygous mice were used to establish JNK1-deficient and wild-type JNK1 control strains. Mice were kept in a specific pathogen-free environment
JNK Is Activated in Hepatic Myofibroblasts During Hepatic Fibrogenesis
JNK plays a key role in liver injury after concanavalin A, TNF-α, high-fat diet, acetaminophen intoxication, carcinogen exposure, or ischemia reperfusion injury.9, 11, 12, 13, 14, 15, 16 To test the role of JNK in hepatic wound healing responses to chronic injury, we first analyzed the phosphorylation status of JNK and its target c-Jun in mice following BDL or CCl4 treatment. We observed a strong activation of the JNK pathway as demonstrated by elevated phosphorylated JNK (p-JNK),
Discussion
The activation of JNK occurs in response to a wide array of cellular stress including injury and wound healing responses.31, 32, 33 Moreover, JNK plays an important role in fibroblasts31, 34 and HSCs19, 20 and has been implicated in the regulation of injury in toxic, metabolic, autoimmune, and neoplastic liver disease.9, 11, 13, 14, 15, 16 Data from our study demonstrate for the first time a significant decrease in fibrosis by JNK inhibition in models of toxic and biliary liver fibrosis.
Acknowledgments
The authors thank Dr David Brenner (La Jolla, CA) for providing α-SMA-red fluorescent protein and Coll-GFP mice, Dr Javier Chaves (Valencia, Spain) for information on JNK1 SNPs, and Christina Millan (Barcelona, Spain) for excellent technical support.
S.de M.'s present address is Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
C.H.O.'s present address is University of California at San Diego, La Jolla, California.
References (43)
Mechanisms of hepatic fibrogenesis
Gastroenterology
(2008)- et al.
Regulation and function of the JNK subgroup of MAP kinases
Biochim Biophys Acta
(1997) - et al.
The JNK signal transduction pathway
Curr Opin Cell Biol
(2007) - et al.
c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration
Hepatology
(2003) - et al.
IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNF-α
Immunity
(2003) - et al.
Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway
J Biol Chem
(2006) - et al.
JNK mediates hepatic ischemia reperfusion injury
J Hepatol
(2005) - et al.
c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity
Gastroenterology
(2006) - et al.
Transforming growth factor-β and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury
Am J Pathol
(2005) - et al.
TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells
Hepatology
(2001)
Inhibition of inhibitor of κB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis
Gastroenterology
Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis
J Hepatol
Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing
J Biol Chem
JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs
Dev Biol
Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation
Mol Cell
Divergent transforming growth factor-β signaling in hepatic stellate cells after liver injury: functional effects on ECE-1 regulation
Am J Pathol
Liver fibrosis
J Clin Invest
Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain
Genes Dev
Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases
Microbiol Mol Biol Rev
Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 down-regulation
J Clin Invest
Differential requirement for c-Jun NH2-terminal kinase in TNF-α- and Fas-mediated apoptosis in hepatocytes
FASEB J
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by grants U54CA126513 (PI of Project 2; to R.F.S.); DK076920 (to R.F.S.); and the 2008 Charles Trey, MD, Memorial Postdoctoral Research Fellowship from the American Liver Foundation (to J.K.).