AJP - Gastrointestinal and Liver Physiology, Vol 272, Issue 2 281-G288, Copyright © 1997 by American Physiological Society

ARTICLES

A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB

A. Mirza, S. L. Liu, E. Frizell, J. Zhu, S. Maddukuri, J. Martinez, P. Davies, R. Schwarting, P. Norton and M. A. Zern
Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.

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.

This article has been cited by other articles:

				R. Nardacci, O. Lo Iacono, F. Ciccosanti, L. Falasca, M. Addesso, A. Amendola, G. Antonucci, A. Craxi, G. M. Fimia, V. Iadevaia, et al. Transglutaminase Type II Plays a Protective Role in Hepatic Injury Am. J. Pathol., April 1, 2003; 162(4): 1293 - 1303. [Abstract] [Full Text] [PDF]

				I. P. Uray, P. J. A. Davies, and L. Fésüs Pharmacological Separation of the Expression of Tissue Transglutaminase and Apoptosis after Chemotherapeutic Treatment of HepG2 Cells Mol. Pharmacol., June 1, 2001; 59(6): 1388 - 1394. [Abstract] [Full Text]

				R C BENYON and J P IREDALE Is liver fibrosis reversible? Gut, April 1, 2000; 46(4): 443 - 446. [Full Text] [PDF]

				G. K. Rangan, Y. Wang, Y.-C. Tay, and D. C. H. Harris Inhibition of NFkappa B activation with antioxidants is correlated with reduced cytokine transcription in PTC Am J Physiol Renal Physiol, November 1, 1999; 277(5): F779 - F789. [Abstract] [Full Text] [PDF]

				T. S. JOHNSON, N. J. SKILL, A. M. EL NAHAS, S. D. OLDROYD, G. L. THOMAS, J. A. DOUTHWAITE, J. L. HAYLOR, and M. GRIFFIN Transglutaminase Transcription and Antigen Translocation in Experimental Renal Scarring J. Am. Soc. Nephrol., October 1, 1999; 10(10): 2146 - 2157. [Abstract] [Full Text]

				A M. I MOWAT Dietary modifications: food dependent autoimmunity in coeliac disease Gut, November 1, 1998; 43(5): 599 - 600. [Full Text] [PDF]

				G. S. Kuncio, M. Tsyganskaya, J. Zhu, S.-L. Liu, L. Nagy, V. Thomazy, P. J. A. Davies, and M. A. Zern TNF-alpha modulates expression of the tissue transglutaminase gene in liver cells Am J Physiol Gastrointest Liver Physiol, February 1, 1998; 274(2): G240 - G245. [Abstract] [Full Text] [PDF]