Leptin, a pleiotropic 16 kDa peptide hormone product of the
ob gene, is secreted predominantly by adipose tissue and well
recognized for its role in the maintenance of body mass and
energy expenditure (1-3). Moreover, advances in understanding
the functional role of leptin in the processes affecting various
tissues throughout the body, have brought to the forefront the
importance of the local release of this cytokine to the processes
of mucosal defense and repair (4-7). Consistent with its
pluripotent nature, leptin and leptin receptors have been
identified in oral mucosa, saliva, and the acinar cells of salivary
glands (8). Leptin released locally within the mucosal tissue has
been implicated in the interaction with proinflammatory
cytokines, regulation of NO production, and the modulation of
arachidonic acid generation by impacting the events of cytosolic
phospholipase A2(cPLA2) activation (6, 7, 9-11). The increase in
leptin level characterizes oral mucosal responses to injury, and
the exogenous leptin is known to accelerate wound repair, and
protects the acinar cells of salivary glands against cytotoxic
effects of ethanol (7, 11, 12).
The oral mucosal responses to ethanol cytotoxicity are
manifested by the elevation in proinflammatory cytokine
production, enhancement in epithelial cell apoptosis,
disturbances in epidermal growth factor and nitric oxide
signaling pathways, and the impairment in prostaglandin
generation, (13-15). Moreover, salivary glands of alcoholics and
animals exposed to ethanol display the evidence of fatty
infiltration, acinar cell swelling, and change in cytoplasm
vacuolation accompanied by cellular degeneration and even
atrophy (16, 17). Interestingly, recent evidence indicates that the
critical event responsible for rapid changes in prostaglandin
production is the selective channeling of arachidonic acid
substrate, released from membrane glycerophospholipids by the
action of cPLA2enzyme, to the site of cyclooxygenase-2 (COX-
2) action for prostaglandin synthesis (18, 19). The activity of
cPLA2 is tightly regulated by post-translational mechanism
involving MAPK/ERK-dependent enzyme protein
phosphorylation and calcium influx that facilitate the enzyme
translocation from cytosol to phospholipid-rich membrane (20,
21). There are also reports suggesting that cPLA2is a downstream
effector of ERK in leptin signaling through Src, and that leptin-
induced responses mediated by ERK involve epidermal growth
factor receptor (EGFR) transactivation (22-24).
Review of the pertinent literature indicates that the signaling
cross-talk involving EGFR transactivation is implicated in the
regulation of a wide variety of cell functions of significance to
oral mucosal repair and integrity maintenance, including cellular
proliferation, differentiation, survival, and migration to the site
of injury (24, 25). In general, the signals triggered by EGFR
JOURNAL OF PHYSIOLOGYAND PHARMACOLOGY 2009, 60, 2, 49-55
B.L. SLOMIANY, A. SLOMIANY
ROLE OF EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION
IN THE ACTIVATION OF CYTOSOLIC PHOSPHOLIPASE A2IN LEPTIN PROTECTION
OF SALIVARY GLAND ACINAR CELLS AGAINST ETHANOL CYTOTOXICITY
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA
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 A2(cPLA2) activity, and characterized by a marked
increase in matrix metalloproteinase MMP-9 and arachidonic acid (AA) release, and PGE2generation. 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 cPLA2 activity, AA release, and PGE2generation. The changes caused by leptin in EGFR
phosphorylation, MMP-9, and cPLA2 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 cPLA2 activation and up-regulation in PGE2 generation, thus providing new insights into the
mechanism of oral mucosal protection against ethanol toxicity.
Keywords: leptin, ethanol cytotoxicity, salivary gland, EGFR transactivation, cPLA2activation, prostaglandin E2
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Received: September 11, 2008
Accepted: April 30, 200
Author’s address: Dr. B.L. Slomiany, Research Center,
C875, UMDNJ-NJ Dental School, 110 Bergen Street, PO Box
1709, Newark, NJ 07103 - 2400, USA; Phone 973 -972-7052;
Fax: 973-972-7020; e-mail: email@example.com