Chinnasamy Thirunavukkarasu and Tadahiro Uemura contributed equally to this study.
Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes†
Article first published online: 12 APR 2005
Copyright © 2005 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 204, Issue 2, pages 654–665, August 2005
How to Cite
Thirunavukkarasu, C., Uemura, T., Wang, L. F., Watkins, S. C. and Gandhi, C. R. (2005), Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J. Cell. Physiol., 204: 654–665. doi: 10.1002/jcp.20366
- Issue published online: 26 MAY 2005
- Article first published online: 12 APR 2005
- Manuscript Accepted: 8 DEC 2004
- Manuscript Received: 31 AUG 2004
- NIH. Grant Number: DK 54411
Endotoxin is implicated in the pathology of acute liver failure. The mechanisms of its actions on quiescent hepatic stellate cells (qHSCs) and their implications in hepatocyte injury are incompletely understood. We investigated effects of endotoxin (bacterial lipopolysaccharide; LPS) on qHSCs and subsequently on hepatocytes. After overnight culture following their isolation, qHSCs were incubated with or without endotoxin for 24 h. The cells and the culture supernatant were analyzed for cytokines and nitric oxide (NO) synthesis. The effects of qHSC-conditioned media on hepatocytes were then determined. LPS increased inducible NO synthase expression, stimulated NO synthesis, and inhibited DNA synthesis in qHSCs. qHSC-conditioned medium inhibited DNA synthesis in hepatocytes without affecting NO synthesis, while LPS (1–1,000 ng/ml)-conditioned qHSC medium stimulated NO synthesis and caused further inhibition of DNA synthesis and apoptosis. These effects of LPS were more pronounced when qHSCs were incubated with serum, but not with LPS-binding protein (LBP) although CD14 (a receptor for LPS-LBP complex) was found in qHSCs. LPS stimulated the synthesis of TNF-α, interleukin (IL)-6, and IL-1β but not of TGF-β in qHSCs. Individually or together, L-NG-monomethylarginine and antibodies to IL-1β, IL-6, and TNF-α only partly reversed qHSC + LPS-conditioned medium-induced inhibition of DNA synthesis in hepatocytes. These results suggest that the effects of LPS on qHSCs are novel, occurring without the aid of LBP/CD14. They also indicate that other factors, in addition to NO, TGF-β, TNF-α, IL-1β, and IL-6 are involved in the mechanisms of the growth inhibitory effects of qHSCs on hepatocytes. © 2005 Wiley-Liss, Inc.