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Interferon‐beta derived from endotoxin‐stimulated hepatic stellate cells causes hepatocyte injury via JNK‐mediated IRF‐1 expression
Author(s) -
Huang Chao,
Yang Shuting,
Geller David,
Stolz Donna Beer,
Gandhi Chandrashekhar
Publication year - 2011
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.25.1_supplement.794.11
Heptatic stellate cells (HSC) produce several growth factors and cytokines that can influence survival and functions of adjacently located hepatocytes, Indeed, soluble mediators elaborated by endotoxin (lipopolysaccharide; LPS)‐stimulated HSC causes (endoplasmic reticulum) ER stress and low level apoptosis of hepatocytes. This injury is not mediated by TNF‐alpha, IL6, IL1‐beta, TGF‐beta or nitric oxide produced by HSC. Thus the precise mediator(s) in LPS/HSC medium and the mechanisms of hepatocyte injury are yet to be determined. Here we found that LPS administration to rats causes nuclear translocation of interferon‐regulatory factor 1 (IRF1), a key event in ischemia/reperfusion injury, in association with ER stress and autophagy. LPS induced expression of IFN‐beta in HSCs. LPS‐conditioned HSC medium as well as IFN‐beta caused activation of JNK‐MAPK, nuclear IRF1 translocation, ER stress and low level apoptosis of hepatocytes. LPS/HSC‐induced IRF‐1 nuclear translocation and apoptosis of hepatocytes were abrogated by inhibitor of JNK‐MAPK activation. Furthermore, suppression of autophagy by 3‐methyladenine exacerbated LPS/HSC‐induced ER stress and profoundly increased apoptosis of hepatocytes. Our results indicate that HSC‐derived IFN‐beta is a critical mediator of hepatocyte injury in pathologies involving increased LPS. (Support: NIH PO1A1081678)