Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression.
OBJECTIVE
Interleukin-6 stimulates liver regeneration and promotes hepatoprotection following experimental liver injury, but underlying mechanisms have not been fully characterized. Because studies suggest matrix metalloproteinase-2 (MMP-2) may promote liver injury, we examined whether IL-6 exerted its protective effects via regulation of MMP-2.


METHODS
MMP-2 was analyzed in livers of IL-6-/- and IL-6+/+ mice following CCl(4) administration. IL-6-/- mice were pretreated with IL-6 and liver histology and MMP-2 expression were examined after liver injury. IL-6-/- mice were treated with an MMP-2 inhibitor and assessment of injury (histology and serum ALT levels), apoptosis by TUNEL assay, and hepatocyte proliferation by BRDU-labeling was performed. These studies were complemented by analysis of cultured stellate cells.


RESULTS
MMP-2 mRNA, protein, and activity was increased in IL-6-/- livers. Restoration of IL-6 signaling in IL-6-/- mice rescued injury and restored MMP-2 expression to wild-type levels. Furthermore, pharmacologic inhibition of MMP-2 decreased hepatocellular injury and apoptosis in IL-6-/- mice. In cultured stellate cells, recombinant IL-6 suppressed endogenous MMP-2 mRNA and protein expression.


CONCLUSIONS
IL-6 may be hepatoprotective in acute injury through down-regulation of MMP-2. These findings suggest a role for MMP-2 in amplifying liver injury in vivo.
Bansal
Meena B
MB
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA. meena.bansal@mssm.edu
Kovalovich
Kellen
K
Gupta
Ritu
R
Li
Wei
W
Agarwal
Akansha
A
Radbill
Brian
B
Alvarez
Carlos E
CE
Safadi
Rifaat
R
Fiel
M Isabel
MI
Friedman
Scott L
SL
Taub
Rebecca A
RA
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009336:Necrosis; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D002251:Carbon Tetrachloride; D020778:Matrix Metalloproteinase 2