Mechanisms of interleukin-6 protection against ischemia-reperfusion injury in rat liver.
Numerous animal studies simulating liver injury have demonstrated that interleukin-6 (IL-6) exerts a protective effect. This study was designed to further analyze the molecular mechanisms underlying the protective role of IL-6 in a rat model of liver ischemia/reperfusion injury. We show that IL-6: (i) at high doses reduces cell damage which occurs in ischemic-reperfused liver, while at low doses displays only a limited protective capacity, (ii) anticipates and enhances hepatocyte compensatory proliferation seen in ischemic-reperfused liver also at a low, more pharmacologically acceptable dose, (iii) sustains the acute phase response which is dampened in ischemic-reperfused liver, (iv) strengthens the heat shock-stress response shown by ischemic-reperfused liver and (v) overcomes the dysfunctions of the unfolding protein response found in ischemic-reperfused liver. We also show that IL-6-enhanced STAT3 activation probably plays a crucial role in the potentiation of the different protective pathways activated in ischemic-reperfused liver. Our data confirm that IL-6 is a potential therapeutic in liver injury of different etiologies and reveal novel mechanisms by which IL-6 sustains liver function after ischemia/reperfusion injury.
Tiberio
Laura
L
Department of Biomedical Sciences and Biotechnology, Division of General Pathology and Immunology, University of Brescia, Italy.
Tiberio
Guido A M
GA
Bardella
Lidia
L
Cervi
Edoardo
E
Cerea
Katia
K
Dreano
Michel
M
Garotta
Gianni
G
Fra
Anna
A
Montani
Nadia
N
Ferrari-Bravo
Andrea
A
Callea
Francesco
F
Grigolato
Piergiovanni
P
Giulini
Stefano M
SM
Schiaffonati
Luisa
L
D000210:Acute-Phase Reaction; D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D018869:Heat-Shock Response / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D011489:Protein Denaturation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000378:metabolism
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D004247:DNA