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Soluble mediators from endotoxin‐stimulated stellate cells cause sustained JNK activation, ER stress and apoptosis of hepatocytes
Author(s) -
Gandhi Chandrashekhar R,
Huang Chao,
Stolz Donna,
Harvey Stephen AK,
Wu Tong
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.236.11
Subject(s) - unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , apoptosis , p38 mitogen activated protein kinases , chop , mapk/erk pathway , hepatic stellate cell , chemistry , programmed cell death , signal transduction , biology , endocrinology , biochemistry
Cells respond to various injurious stimuli by undergoing endoplasmic reticulum (ER) stress that is utilized as a survival or death mechanism. Bacterial lipopolysaccharide (LPS)‐stimulated hepatic stellate cells (HSCs) produce mediators that inhibit DNA synthesis and induce apoptosis of hepatocytes. Our objective was to investigate whether (a) LPS causes ER stress and apoptosis of hepatocytes in vivo, and (b) soluble mediators released by LPS‐stimulated HSCs cause ER stress leading to apoptosis of hepatocytes in vitro. LPS (10 mg/kg; ip) treatment of rats for 6h was found to cause ER stress/autophagy, activation of JNK MAPK and activation/expression of ER stress‐related molecules PERK, eIF2á and CHOP, and activation of caspase‐3 in hepatocytes. In vitro, soluble mediators released by LPS (10–1000ng/ml)‐stimulated HSCs in serum‐free condition caused cytosolic vacuolization associated with activation/increased expression of PERK, eIF2á and CHOP. LPS‐stimulated HSCs also caused activation of p38‐ and JNK‐MAPK in hepatocytes. However, blockage of JNK but not p38 activation ameliorated ER stress, inhibition of DNA synthesis and caspase‐3 activation caused by LPS‐stimulated HSCs. The results suggest that the ER stress induced by mediators released by LPS‐stimulated HSCs in hepatocytes may be an important mechanism that dictates their survival or death. Supported by an NIH grant (DK 54411).