FK506 enhances fibrogenesis in in vitro and in vivo models of liver fibrosis in rats.
OBJECTIVE
The immunosuppressant FK506 is undergoing clinical trials in transplantation and autoimmune diseases. FK506 modulates several cytokines and exerts hepatoprotection in acute models. This study was initiated to determine whether FK506 would be beneficial as an antifibrogenic agent.


METHODS
Fibrosis was induced by carbon tetrachloride administration to rats. Half of those animals were treated with FK506. The rats were killed after 8 weeks of carbon tetrachloride treatment. The livers were evaluated by histology, Northern hybridizations, and collagen quantitation. Additionally, rat fibroblasts were incubated with and without FK506 and used for Northern hybridization analysis.


RESULTS
Surprisingly, FK506 exacerbated hepatic inflammation and fibrosis. Increased hepatic collagen and higher messenger RNA levels of transforming growth factor beta 1 and collagens I, III, and IV were found in the FK506-treated group. Rat fibroblasts treated with FK506 expressed higher levels of collagens I and III, fibronectin, macrophage-colony stimulating factor, tissue inhibitor of metalloprotease, and transforming growth factor beta 1 messenger RNAs.


CONCLUSIONS
These findings suggest that FK506 increases the expression of extracellular matrix genes and enhances fibrosis in the rat model. While further studies are needed to elucidate these profibrogenic mechanisms, caution is indicated for the unrestricted use of FK506 in patients subject to recurrent fibrogenic stimulation.
Frizell
E
E
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Abraham
A
A
Doolittle
M
M
Bashey
R
R
Kresina
T
T
Van Thiel
D
D
Zern
M A
MA
D000818:Animals; D015152:Blotting, Northern; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen; D016559:Tacrolimus