Hepatic Medicine: Evidence and Research
Dr Webster (Logout)
Open access peer-reviewed scientific and medical journals.
Dove Medical Press is now a member of the Open Access Initiative
An Author's Guide
A guide to help authors get their paper published.
Support Open Access and Dove Press
Promotional Article Monitoring - further details
Favored Author Program
Real benefits for authors, including fast-track processing of papers.
Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
(4450) Total Article Views
Authors: Kathleen Ponzetti, Melissa King, Anna Gates, et al
Published Date January 2010
Volume 2010:2 Pages 1 - 11
Kathleen Ponzetti1, Melissa King1, Anna Gates1, M Sawkat Anwer2, Cynthia RL Webster1
1Department of Clinical Science, Tufts Cummings School of Veterinary Medicine, Grafton MA, USA; 2Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Grafton MA, USA
Abstract: Lipopolysaccharide (LPS) is known to damage hepatocytes by cytokines released from activated Kupffer cells, but the ancillary role of LPS as a direct hepatotoxin is less well characterized. The aim of this study was to determine the direct effect of LPS on hepatocyte viability and the underlying signaling mechanism. Rat hepatocyte cultures treated overnight with LPS (500 ng/mL) induced apoptosis as monitored morphologically (Hoechst 33258) and biochemically (cleavage of caspase 3 and 9 and the appearance of cytochrome C in the cytoplasm). LPS-induced apoptosis was additive to that induced by glycochenodeoxycholate or Fas ligand, was associated with activation of c-Jun N-terminal kinase B (JNK) and p38 mitogenactivated protein kinases (MAPK), and inhibition of protein kinase (AKT). Inhibition of JNK by SP600125, but not of p38 MAPK by SB203580 attenuated LPS-induced apoptosis, indicating JNK dependency. CPT-2-Me-cAMP, an activator of cAMP-GEF, decreased apoptosis due to LPS alone or in combination with glycochenodeoxycholate or Fas ligand. CPT-2-Me-cAMP also prevented LPS-induced activation of JNK and inhibition of AKT. Taken together, these results suggest that LPS can induce hepatocyte apoptosis directly in vitro in a JNK-dependent manner and activation of cAMP-GEF protects against the LPS-induced apoptosis most likely by reversing the effect of LPS on JNK and AKT.
Keywords: apoptosis, cAMP-GEF, AKT, exchange protein activated by cAMP (EPAC), lipopolysaccharide, JNK
Cannotea Citeulike Del.icio.us Facebook LinkedIn Twitter
Readers of this article also read:
"You do a tremendous job!!" Ruben Restrepo, University of Texas Health Science Center, San Antonio.
- Amino acid-responsive Crohn's disease: a case study
- Retrospective analysis of KRAS status in metastatic colorectal cancer patients: a single-center feasibility study
- Oropharyngeal Crohn’s disease
- Methylnaltrexone in the treatment of opioid-induced constipation