Leptin-induced cytosolic phospholipase A2 activation in gastric mucosal protection against ethanol cytotoxicity involves epidermal growth factor receptor transactivation

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8 Citations (Scopus)

Abstract

A pluripotent cytokine, leptin, released locally within the mucosal tissue is an important mediator of the processes of gastric mucosal defense and repair. Here, we report that leptin protection of gastric mucosal cells against ethanol cytotoxicity requires epidermal growth factor receptor (EGFR) participation. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR and cPLA2 phosphorylation, and characterized by a marked increase in arachidonic acid (AA) release and prostaglandin (PGE2) generation. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with Src kinase inhibitor, PP2, and EGFR kinase inhibitor, AG1478, as well as ERK inhibitor, PD98059. Moreover, all three agents evoked also the inhibition in leptin-induced upregulation in cPLA2 activity, AA release, and PGE2 generation. Furthermore, changes caused by leptin in EGFR phosphorylation and cPLA2 activation were susceptible to suppression by GM6001, a metalloprotease inhibitor of membrane-anchored EGFR ligand cleavage. These findings disclose an important link between leptin-induced and Src kinase-mediated EGFR transactivation and the activation of cytosolic phospholipase A2 that leads to up-regulation in PGE2 production, thus providing new insights into the mechanism of gastric mucosal protection by leptin.

Original languageEnglish (US)
Pages (from-to)6-14
Number of pages9
JournalInflammopharmacology
Volume17
Issue number1
DOIs
StatePublished - Feb 1 2009

Fingerprint

Cytosolic Phospholipases A2
Leptin
Epidermal Growth Factor Receptor
Transcriptional Activation
Stomach
Ethanol
Dinoprostone
src-Family Kinases
Arachidonic Acid
Up-Regulation
Phosphorylation
Metalloproteases
Prostaglandins
Mucous Membrane
Cytokines
Ligands
Membranes

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology
  • Pharmacology (medical)

Keywords

  • EGFR transactivation
  • Ethanol cytotoxicity
  • Gastric mucosal protection
  • Leptin
  • PGE2
  • Src
  • cPLA

Cite this

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abstract = "A pluripotent cytokine, leptin, released locally within the mucosal tissue is an important mediator of the processes of gastric mucosal defense and repair. Here, we report that leptin protection of gastric mucosal cells against ethanol cytotoxicity requires epidermal growth factor receptor (EGFR) participation. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR and cPLA2 phosphorylation, and characterized by a marked increase in arachidonic acid (AA) release and prostaglandin (PGE2) generation. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with Src kinase inhibitor, PP2, and EGFR kinase inhibitor, AG1478, as well as ERK inhibitor, PD98059. Moreover, all three agents evoked also the inhibition in leptin-induced upregulation in cPLA2 activity, AA release, and PGE2 generation. Furthermore, changes caused by leptin in EGFR phosphorylation and cPLA2 activation were susceptible to suppression by GM6001, a metalloprotease inhibitor of membrane-anchored EGFR ligand cleavage. These findings disclose an important link between leptin-induced and Src kinase-mediated EGFR transactivation and the activation of cytosolic phospholipase A2 that leads to up-regulation in PGE2 production, thus providing new insights into the mechanism of gastric mucosal protection by leptin.",
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N2 - A pluripotent cytokine, leptin, released locally within the mucosal tissue is an important mediator of the processes of gastric mucosal defense and repair. Here, we report that leptin protection of gastric mucosal cells against ethanol cytotoxicity requires epidermal growth factor receptor (EGFR) participation. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR and cPLA2 phosphorylation, and characterized by a marked increase in arachidonic acid (AA) release and prostaglandin (PGE2) generation. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with Src kinase inhibitor, PP2, and EGFR kinase inhibitor, AG1478, as well as ERK inhibitor, PD98059. Moreover, all three agents evoked also the inhibition in leptin-induced upregulation in cPLA2 activity, AA release, and PGE2 generation. Furthermore, changes caused by leptin in EGFR phosphorylation and cPLA2 activation were susceptible to suppression by GM6001, a metalloprotease inhibitor of membrane-anchored EGFR ligand cleavage. These findings disclose an important link between leptin-induced and Src kinase-mediated EGFR transactivation and the activation of cytosolic phospholipase A2 that leads to up-regulation in PGE2 production, thus providing new insights into the mechanism of gastric mucosal protection by leptin.

AB - A pluripotent cytokine, leptin, released locally within the mucosal tissue is an important mediator of the processes of gastric mucosal defense and repair. Here, we report that leptin protection of gastric mucosal cells against ethanol cytotoxicity requires epidermal growth factor receptor (EGFR) participation. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR and cPLA2 phosphorylation, and characterized by a marked increase in arachidonic acid (AA) release and prostaglandin (PGE2) generation. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with Src kinase inhibitor, PP2, and EGFR kinase inhibitor, AG1478, as well as ERK inhibitor, PD98059. Moreover, all three agents evoked also the inhibition in leptin-induced upregulation in cPLA2 activity, AA release, and PGE2 generation. Furthermore, changes caused by leptin in EGFR phosphorylation and cPLA2 activation were susceptible to suppression by GM6001, a metalloprotease inhibitor of membrane-anchored EGFR ligand cleavage. These findings disclose an important link between leptin-induced and Src kinase-mediated EGFR transactivation and the activation of cytosolic phospholipase A2 that leads to up-regulation in PGE2 production, thus providing new insights into the mechanism of gastric mucosal protection by leptin.

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