A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB.
This study was undertaken to delineate a possible role for tissue transglutaminase (tTG), an enzyme that catalyzes protein cross-linking, in hepatic fibrogenesis. Rats were treated with CCl4 solution and then killed at different stages of liver injury and fibrogenesis. Liver tTG mRNA levels were markedly increased as early as 6 h after the first injection, peaked at 4 days and 1 wk, and remained increased for 8 wk. The enzymatic activity of tTG was increased in livers of rats treated with CCl4, in a fashion that paralleled the Northern blot results. Cell isolation experiments indicated that all hepatic cell types synthesize tTG mRNA. Increased binding to the nuclear factor-kappaB (NF-kappaB) motif of the tTG promoter was found in the nuclear extracts prepared from CCl4-treated samples. These data demonstrate an increase in tTG gene expression during hepatic injury and fibrosis, suggesting a possible role for this enzyme in stabilizing the fibrotic bands during hepatic fibrogenesis. Moreover, increased NF-kappaB binding to the tTG promoter may represent one of the mechanisms by which cell injury induces tTG transcription and thus potentiates the process of fibrogenesis.
Mirza
A
A
Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Liu
S L
SL
Frizell
E
E
Zhu
J
J
Maddukuri
S
S
Martinez
J
J
Davies
P
P
Schwarting
R
R
Norton
P
P
Zern
M A
MA
D000818:Animals; D015152:Blotting, Northern; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016328:NF-kappa B; D012333:RNA, Messenger; D011503:Transglutaminases