Premium
Mechanisms of endotoxin‐induced NO, IL‐6, and TNF‐α production in activated rat hepatic stellate cells: Role of p38 MAPK
Author(s) -
Thirunavukkarasu Chinnasamy,
Watkins Simon C.,
Gandhi Chandrashekhar R.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21254
Subject(s) - pyrrolidine dithiocarbamate , p38 mitogen activated protein kinases , hepatic stellate cell , proinflammatory cytokine , tumor necrosis factor alpha , mapk/erk pathway , kinase , phosphorylation , signal transduction , cytokine , microbiology and biotechnology , protein kinase a , biology , chemistry , medicine , nf κb , endocrinology , immunology , inflammation
Compelling experimental evidence indicates that the interactions between endotoxin and hepatic stellate cells (HSCs) can play a significant role in the pathogenesis of liver disease. Endotoxin‐induced release of a multifunctional mediator NO (via inducible NO synthase) and the proinflammatory cytokines tumor necrosis factor α (TNF‐α) and interleukin (IL)‐6 by HSCs could be an important mechanism of pathological changes in the liver. However, the signaling mechanisms of these effects are poorly understood. In this study, we found that endotoxin causes activation of mitogen‐activated protein kinases (MAPKs) (extracellular signal‐regulated protein kinase [ERK] 1 and 2, p38, and c‐Jun NH2‐terminal kinase [JNK]) and nuclear factor κB (NF‐κB) and production of H 2 O 2 in culture‐activated HSCs. However, only p38 and NF‐κB were found to be responsible for the synthesis of NO, IL‐6, and TNF‐α. Exogenous H 2 O 2 caused modest stimulation of TNF‐α synthesis, did not affect the synthesis of NO or IL‐6, and did not activate NF‐κB or MAPKs. Inhibition of p38 and NF‐κB activation by SB203580 and pyrrolidine dithiocarbamate, respectively, blocked endotoxin‐induced H 2 O 2 , NO, TNF‐α, and IL‐6 synthesis. Inhibition of ERK1/2 and JNK phosphorylation did not alter these effects of endotoxin. Whereas SB203580 inhibited endotoxin‐induced NF‐κB activation, pyrrolidine dithiocarbamate did not affect p38 phosphorylation in endotoxin‐stimulated cells. In conclusion , endotoxin‐induced synthesis of NO, TNF‐α, and IL‐6 in HSCs is mediated by p38 and NF‐κB, with involvement of H 2 O 2 in TNF‐α production. (H EPATOLOGY 2006;44:389–398.)