TAK1/JNK and p38 have opposite effects on rat hepatic... : Hepatology (original) (raw)

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Schnabl, Bernd1, 2; Bradham, Cynthia A.2; Bennett, Brydon L.3; Manning, Anthony M.3; Stefanovic, Branko2; Brenner, David A. M.D.*,1,2

1Departments of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC

2Departments of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC

3Signal Research Division of Celgene Incorporation, San Diego, CA

E-mail: [email protected]

*Address reprint requests to: Department of Medicine, Division of Digestive Diseases and Nutrition, CB# 7038, Glaxo Research Bldg. Rm. 156, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. fax: 919-966-7468

Received April 25, 2001; accepted August 16, 2001; previously published online December 30, 2003

Abstract

After liver injury, hepatic stellate cells (HSCs) undergo a process of activation with expression of smooth muscle α-actin (α-SMA), an increased proliferation rate, and a dramatic increase in synthesis of type I collagen. The intracellular signaling mechanisms of activation and perpetuation of the activated phenotype in HSCs are largely unknown. In this study the role of the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38, were evaluated in primary cultures of rat HSCs. The effect of JNK was assessed by using an adenovirus expressing a dominant negative form of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) (Ad5dnTAK1) and a new selective pharmacologic inhibitor SP600125. The effect of p38 was assessed with the selective pharmacologic inhibitor SB203580. These kinases were inhibited starting either in quiescent HSCs (culture day 1) or in activated HSCs (culture day 5). Although blocking TAK1/JNK and p38 decreased the expression of α-SMA protein in early stages of HSC activation, no effect was observed when TAK1/JNK or p38 were inhibited in activated HSCs. JNK inhibition increased and p38 inhibition decreased collagen α1(I) mRNA level as measured by RNase protection assays, with maximal effects observed in early stages of HSC activation. Furthermore, TAK1/JNK inhibition decreased HSC proliferation, whereas p38 inhibition led to an increased proliferation rate of HSCs, independently of its activation status. These results show novel roles for the TAK1/JNK pathway and p38 during HSC activation in culture. Despite similar activators of TAK1/JNK and p38, their functions in HSCs are distinct and opposed.