Slomiany B L, Slomiany A
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA.
J Physiol Pharmacol. 2009 Jun;60(2):49-55.
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.
瘦素是一种多效激素，由唾液腺腺泡细胞分泌到唾液中，是口腔黏膜防御过程的重要介质。在此，我们报告表皮生长因子受体（EGFR）转活化在介导瘦素保护舌下唾液腺腺泡细胞免受乙醇细胞毒性的信号事件中的作用。我们发现，瘦素对乙醇细胞毒性的保护作用与EGFR蛋白酪氨酸激酶和胞质磷脂酶A2（cPLA2）活性增加有关，其特征是基质金属蛋白酶MMP-9和花生四烯酸（AA）释放显著增加以及PGE2生成增加。使用JAK抑制剂AG490、Src抑制剂PP2、EGFR抑制剂AG1478以及ERK抑制剂PD98059可使瘦素抵抗乙醇细胞毒性的能力丧失。此外，这些药物还可抑制瘦素诱导的cPLA2活性、AA释放和PGE2生成上调。瘦素引起的EGFR磷酸化、MMP-9和cPLA2活化的变化易被金属蛋白酶抑制剂GM6001抑制，但MMP-9的产生不受EGFR抑制剂AG1478或PKC抑制剂Ro318220影响。这些发现表明MMP-9参与了瘦素诱导的EGFR转活化事件，该事件导致信号级联反应，进而导致cPLA2活化和PGE2生成上调，从而为口腔黏膜抵抗乙醇毒性的机制提供了新的见解。
