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TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells
Author(s) -
Schnabl Bernd,
Bradham Cynthia A.,
Bennett Brydon L.,
Manning Anthony M.,
Stefanovic Branko,
Brenner David A.
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.28790
Subject(s) - hepatic stellate cell , p38 mitogen activated protein kinases , kinase , microbiology and biotechnology , mitogen activated protein kinase , c jun , protein kinase a , biology , chemistry , endocrinology , biochemistry , transcription factor , gene
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.