Abstract
Phospholipase Cγ2 (PLCγ2) plays a pivotal role in mediation of inflammatory reaction to bacterial lipopolysaccharide (LPS) as well as serves as a key target in modulatory influence of the hormone ghrelin. Here we explore the involvement of Rac1 and its activator, guanine nucleotide exchange factor (GEF), Dock180, in mediation of PLCγ2 activation in salivary gland acinar cells in response to P. gingivalis LPS and ghrelin. We show that stimulation of the acinar cells with the LPS leads to up-regulation in Dock and PLCγ2 activation, and is reflected in the membrane translocation of Rac1 and PLCγ2, while the effect of ghrelin is manifested by the suppression in Rac1 translocation. Further, we reveal that stimulation with the LPS leads to Dock180 phosphorylation on Tyr and Ser, while the modulatory influence of ghrelin, manifested by a drop in membrane Rac1-GTP, is asso-ciated with a distinct decrease in Dock180 phosphorylation on Ser. Moreover, we demonstrate that phosphorylation on Tyr remains under the control of Src kinase and is accompanied by Dock180 membrane translocation, while protein kinase Cδ(PKCδ) is involved in the LPS-induced phosphorylation of the membrane-recruited Dock180 on Ser. Thus, our findings underscore the role of Src/PKCδ-mediated GEF Dock180 phosphorylation on Tyr/Ser in modulation of salivary gland acinar cell PLCγ2 activation in response to P. gingivalis as well as ghrelin.
Highlights
Porphyromonas gingivalis, a Gram-negative bacterium found in periodontal pockets of people with gum disease, is recognized as a major culprit in the etiology of periodontitis, a chronic inflammatory condition that affects about 15% of adult population and is a major cause of adult tooth loss [1] [2]
Taking into consideration a pivotal role of Phospholipase Cγ2 (PLCγ2) in propagation of proinflammatory reaction to bacterial endotoxins being a primary target in modulatory influence of ghrelin on the extent of oral mucosal inflammatory reaction [5] [6], in this study, we examined the involvement of P. gingivalis LPS in the amplification of PLCγ2 activation associated with the salivary acinar cell Rac1 activation by guanine nucleotide exchange factor (GEF) Dock180
In view of a central role of PLCγ2 in propagation of proinflammatory response to bacterial endotoxins as well as being a key target in modulatory influence of peptide hormone, ghrelin, we investigated the factors affecting the PLCγ2 activation in rat sublingual salivary gland acinar cells exposed to LPS of periodontopathic bacterium, P. gingivalis
Summary
Porphyromonas gingivalis, a Gram-negative bacterium found in periodontal pockets of people with gum disease, is recognized as a major culprit in the etiology of periodontitis, a chronic inflammatory condition that affects about 15% of adult population and is a major cause of adult tooth loss [1] [2]. PLC activation plays a major role in defining the extent of inflammatory response to LPS, but is considered as a primary target in modulatory influence of the hormone ghrelin on the mucosal responses to bacterial invasion [6] [9] [13]-[15] This 28-amino acid peptide, initially isolated from the stomach [16] and subsequently identified in oral mucosa, saliva and the acinar cells of salivary glands [17], is commonly recognized as an important modulator of the processes of mucosal repair and the control of local inflammatory responses to bacterial infection. Engagement by ghrelin of the growth hormone secretagogue receptor type 1a (GHS-R1a), a G protein-coupled receptor (GPCR), leads to activation of heterotrimeric G protein-dependent signal transduction pathways, including PLC/PKC, PI3K, and Src/Akt implicated in signaling to NOgenerating system [6] [13] [14] [18] [19]
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