Role of epidermal growth factor receptor transactivation in the activation of cytosolic phospholipase A(2) in leptin protection of salivary gland acinar cells against ethanol cytotoxicity.
A pleiotropic hormone, leptin, secreted into saliva by the acinar cells of salivary glands is an important mediator of the processes of oral mucosal defense. Here, we report on the role of epidermal growth factor receptor (EGFR) transactivation in the signaling events that mediate leptin protection of sublingual salivary gland acinar cells against ethanol cytotoxicity. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR protein tyrosine kinase and cytosolic phospholipase A(2) (cPLA(2)) activity, and characterized by a marked increase in matrix metalloproteinase MMP-9 and arachidonic acid (AA) release, and PGE(2) generation. The loss in countering capacity of leptin against ethanol cytotoxicity was attained with JAK inhibitor AG490, Src inhibitor PP2, and EGFR inhibitor AG1478, as well as ERK inhibitor PD98059. Moreover, the agents evoked also the inhibition in leptin-induced up-regulation in cPLA(2) activity, AA release, and PGE(2) generation. The changes caused by leptin in EGFR phosphorylation, MMP-9, and cPLA(2) activation were susceptible to suppression by metalloprotease inhibitor GM6001, but the production of MMP-9 was not affected by EGFR inhibitor AG1478 or PKC inhibitor Ro318220. These findings point to the involvement of MMP-9 in the event of leptin-induced EGFR transactivation that results in the signaling cascade leading to cPLA(2) activation and up-regulation in PGE(2) generation, thus providing new insights into the mechanism of oral mucosal protection against ethanol toxicity.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
A
A
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D012469:Salivary Glands / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D020738:Leptin; D061965:Matrix Metalloproteinase Inhibitors; D016718:Arachidonic Acid; D000431:Ethanol; D066246:ErbB Receptors; D053612:Janus Kinases; D019061:src-Family Kinases; D011493:Protein Kinase C; D054510:Phospholipases A2, Cytosolic; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone