IL-6 Promotes compensatory liver regeneration in cirrhotic rat after partial hepatectomy.
Major hepatic resection in cirrhotic patients is associated with impaired liver regeneration and failure, leading to high peri-operative mortality. In this work, the causes of defective regeneration in cirrhotic liver and the utility of IL-6 treatment were investigated in an experimental model combining cirrhosis and partial hepatectomy in the rat. Relative to normal controls, decompensated cirrhotic animals showed decreased survival, while compensated cirrhotic animals showed similar survival but reduced hepatic DNA synthesis and newly regenerated liver mass amount. Defective liver regeneration was associated with a decrease in STAT3 and NF-kB activation, consistent with an increased accumulation of their respective inhibitors PIAS3 and IkBalpha, and with a decreased induction of Bcl-xL. Treatment with recombinant IL-6 enhanced survival of decompensated cirrhotic animals, while it did not affect survival of compensated cirrhotic animals but sustained liver regeneration, by restoring STAT3 and NF-kB activation and Bcl-xL induction to the levels found in normal controls. The pro-growth effects exerted by IL-6 treatment in cirrhotic liver were attained also at low, pharmacologically acceptable doses. In conclusion, our results suggest that IL-6 treatment may be therapeutic in major resection of cirrhotic liver.
Tiberio
Guido A M
GA
Università Campus Bio-Medico, Roma and Surgical Clinic, Department of Medical and Surgical Sciences, Brescia University, Italy.
Tiberio
Laura
L
Benetti
Anna
A
Cervi
Edoardo
E
Montani
Nadia
N
Dreano
Michel
M
Garotta
Gianni
G
Cerea
Katia
K
Steimberg
Nathalie
N
Pandolfo
GianPietro
G
Ferrari-Bravo
Andrea
A
Mazzoleni
Giovanna
G
Giulini
Stefano M
SM
Schiaffonati
Luisa
L
D000818:Animals; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000503:physiopathology* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051020:bcl-X Protein / Q000378:metabolism
C494813:Bcl2l1 protein, rat; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D018832:Molecular Chaperones; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; C112253:Pias3 protein, rat; D050828:Protein Inhibitors of Activated STAT; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha