Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes

Kathleen Ponzetti1, Melissa King1, Anna Gates1, M Sawkat Anwer2, Cynthia RL Webster11Department of Clinical Science, Tufts Cummings School of Veterinary Medicine, Grafton MA, USA; 2Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Grafton MA, USAAbstract: Lipopolysacch...

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Autores principales:	Kathleen Ponzetti, Melissa King, Anna Gates, et al
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2010
Materias:	Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/b865fb4061694ab0a3a586f8f53be70a
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spelling	oai:doaj.org-article:b865fb4061694ab0a3a586f8f53be70a2021-12-02T02:12:21ZCyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes1179-1535https://doaj.org/article/b865fb4061694ab0a3a586f8f53be70a2010-01-01T00:00:00Zhttp://www.dovepress.com/cyclic-amp-guanine-exchange-factor-activation-inhibits-jnk-dependent-l-a3900https://doaj.org/toc/1179-1535Kathleen Ponzetti1, Melissa King1, Anna Gates1, M Sawkat Anwer2, Cynthia RL Webster11Department of Clinical Science, Tufts Cummings School of Veterinary Medicine, Grafton MA, USA; 2Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Grafton MA, USAAbstract: 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 Kathleen PonzettiMelissa KingAnna Gateset alDove Medical PressarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatic Medicine: Evidence and Research, Vol 2010, Iss default, Pp 1-11 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Diseases of the digestive system. Gastroenterology RC799-869 Kathleen Ponzetti Melissa King Anna Gates et al Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
description	Kathleen Ponzetti1, Melissa King1, Anna Gates1, M Sawkat Anwer2, Cynthia RL Webster11Department of Clinical Science, Tufts Cummings School of Veterinary Medicine, Grafton MA, USA; 2Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Grafton MA, USAAbstract: 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
format	article
author	Kathleen Ponzetti Melissa King Anna Gates et al
author_facet	Kathleen Ponzetti Melissa King Anna Gates et al
author_sort	Kathleen Ponzetti
title	Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
title_short	Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
title_full	Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
title_fullStr	Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
title_full_unstemmed	Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
title_sort	cyclic amp-guanine exchange factor activation inhibits jnk-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes
publisher	Dove Medical Press
publishDate	2010
url	https://doaj.org/article/b865fb4061694ab0a3a586f8f53be70a
work_keys_str_mv	AT kathleenponzetti cyclicampguanineexchangefactoractivationinhibitsjnkdependentlipopolysaccharideinducedapoptosisinrathepatocytes AT melissaking cyclicampguanineexchangefactoractivationinhibitsjnkdependentlipopolysaccharideinducedapoptosisinrathepatocytes AT annagates cyclicampguanineexchangefactoractivationinhibitsjnkdependentlipopolysaccharideinducedapoptosisinrathepatocytes AT etal cyclicampguanineexchangefactoractivationinhibitsjnkdependentlipopolysaccharideinducedapoptosisinrathepatocytes
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Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes

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