Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver.
OBJECTIVE
Tissue inhibitors of metalloproteinases may contribute to liver fibrosis by preventing remodeling of fibrillar collagens by interstitial collagenase. This hypothesis was investigated by comparing the relative expression of messenger RNA for interstitial collagenase, gelatinase A, and tissue inhibitor of metalloproteinases 1 and 2 in fibrotic and normal human liver.


METHODS
Hepatic expression of metalloproteinases and their inhibitors was examined using ribonuclease protection assay, immunocytochemistry, and immunoassay. Lipocyte expression of tissue inhibitors of metalloproteinases was examined using Northern blotting and reverse zymography.


RESULTS
Messenger RNA levels for tissue inhibitors of metalloproteinase 1 and 2 were elevated to 260%-526% of levels in normal liver in biliary atresia, primary biliary cirrhosis, and primary sclerosing cholangitis. In fibrotic livers, tissue inhibitor of metalloproteinase 1 protein was 367%-724% of normal. Gelatinase A messenger RNA level increased to 324%-430% of normal values in fibrotic liver, but interstitial collagenase messenger RNA level was not significantly altered. Normal human liver lipocytes activated by culture on plastic expressed messenger RNA and protein for tissue inhibitor of metalloproteinase 1 and 2.


CONCLUSIONS
Increased expression of tissue inhibitors of metalloproteinases relative to interstitial collagenase may promote deposition of interstitial collagens in liver fibrosis. Our studies further suggest that lipocytes are an important source of tissue inhibitors of metalloproteinases in progressive liver fibrosis.
Benyon
R C
RC
University of Southampton, Department of Medicine, Southampton General Hospital, England.
Iredale
J P
JP
Goddard
S
S
Winwood
P J
PJ
Arthur
M J
MJ
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018093:Gelatinases / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics; D011480:Protease Inhibitors / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2