Interleukin-6 sustains hepatic regeneration in cirrhotic rat.
OBJECTIVE
In the liver IL-6 displays growth-inducing and pro-survival activities. We studied the pro-proliferative and protective mechanisms of IL-6 treatment in a model of liver cirrhosis in wild type rat, investigating the theoretical basis for a potential pharmacologic role of IL-6 in cirrhosis.


METHODS
We analyzed IL-6 receptors levels in cirrhotic liver. We also studied the activation of signaling pathways downstream IL-6 receptors by analyzing the DNA-binding activity of transcription factors STAT3, AP-1, HNF-1 and NF-kappaB and the phosphorylation status of AKT and eNOS. We also analyzed hepato-cell proliferation, by determining BrdU incorporation into DNA, and liver mass expansion.


RESULTS
We show that liver cells from cirrhotic animals have increased expression of the IL-6 receptor alpha/gp80. In addition, we show that in cirrhosis the main molecular pathways downstream the receptors are intact and that IL-6 activates STAT3, AP-1 and NF-kappaB transcription factors, induces AKT and eNOS phosphorylation and increases hepato-cell proliferation and liver mass expansion in a dose-dependent manner.


CONCLUSIONS
Our data demonstrate that the theoretical basis exists for the therapeutic employment of IL-6 in liver cirrhosis.
Tiberio
Guido Alberto Massimo
GA
Surgical Clinic, Department of Medical and Surgical Sciences, University of Brescia, Italy. guido.tiberio@libero.it
Tiberio
Laura
L
Benetti
Anna
A
Cervi
Edoardo
E
Pandolfo
Giampietro
G
Dreano
Michel
M
Garotta
Gianni
G
Comini
Laura
L
Martini
Marika
M
Giulini
Stefano Maria
SM
Schiaffonati
Luisa
L
D000818:Animals; D001973:Bromodeoxyuridine / Q000032:analysis; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014157:Transcription Factors; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine