Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis.
OBJECTIVE
The regulation of three major intracellular signalling protein kinases was investigated in two models of liver injury leading to hepatic fibrosis, dimethylnitrosamine administration (DMN) and bile duct ligation (BDL).


METHODS
Extracellular signal-regulated kinases (ERK)1/2, c-Jun terminal kinase (JNK) and p70S6-kinase (p70(S6K)) were studied in vivo in the whole liver, in liver sections and in isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC).


RESULTS
In the whole liver, activation of these kinases occurred with a different kinetic pattern in both models of liver injury. By immunohistochemistry and Western blot in isolated cells, phosphorylated kinases were detected in proliferating cells (i.e. hepatocytes and cholangiocytes after DMN and BDL, respectively), in addition to stellate-like elements. ERK1/2, JNK and p70(S6K) activation was associated with hepatocytes proliferation after DMN, while JNK activation was not associated with cholangiocytes proliferation after BDL. In HSC isolated from injured livers, protein kinases were differentially activated after BDL and DMN. Kinases activation in HSC in vivo preceded cell proliferation and alpha-smooth muscle actin appearance, a marker of HSC transformation in myofibroblast-like cells, and collagen deposition.


CONCLUSIONS
Our findings indicate that these kinases are coordinately regulated during liver regeneration and suggest that their modulation could be considered as a future therapeutic approach in the management of liver damage.
Svegliati-Baroni
Gianluca
G
Clinica di Gastroenterologia, Università di Ancona, Ospedale Regionale Torrette, Via Conca, 60020 Ancona, Italy. g.svegliati@univpm.it
Ridolfi
Francesco
F
Caradonna
Zaira
Z
Alvaro
Domenico
D
Marzioni
Marco
M
Saccomanno
Stefania
S
Candelaresi
Cinzia
C
Trozzi
Luciano
L
Macarri
Giampiero
G
Benedetti
Antonio
A
Folli
Franco
F
D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002455:Cell Division; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000378:metabolism*; D004128:Dimethylnitrosamine; D004789:Enzyme Activation; D022781:Hepatocytes / Q000473:pathology; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction
D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D004128:Dimethylnitrosamine