Role of Protein Kinase C&amp;lt;i&amp;gt;δ&amp;lt;/i&amp;gt;-Mediated Spleen Tyrosine Kinase (Syk) Phosphorylation on Ser in the Amplification of Oral Mucosal Inflammatory Responses to &amp;lt;i&amp;gt;Porphyromonas gingivalis&amp;lt;/i&amp;gt;

Bronislaw L Slomiany,Amalia Slomiany

doi:10.4236/jbm.2018.63005

Abstract

The signaling events underlying oral mucosal inflammatory responses to P. gingivalis and its key endotoxin, lipopolysaccharide (LPS), relay primarily on the LPS engagement of Toll-like receptor-4 (TLR4), and the activation of IκB-kinase complex (IKK) and mitogen-activated protein kinases (MAPKs that exert their control over transcription factors implicated in the regulation of iNOS and COX-2 proinflammatory genes expression). Since spleen tyrosine kinase (Syk) has emerged recently as a major amplifier in the production of proinflammatory mediators, we investigated the process of recruitment and interaction of Syk with TLR4 in salivary gland acinar cells in response to P. gingivalis LPS. Our findings revealed that stimulation of the acinar cells with the LPS leads to protein kinase Cδ (PKCδ)-mediated phosphorylation of Syk on Ser which results in its localization with the membrane associated TLR4 complex and the activation through phosphorylation on Tyr. Further, our results support the involvement of Syk in the amplification of transcription factors involved in the assembly and expression of transcription complexes associated with the induction in COX-2 and iNOS genes. Therefore, our data suggest that PKCδ is a primary linchpin affecting the Syk recruitment to the membrane localized TLR4, and hence affects the efficiency of the kinase activation and the magnitude of oral mucosal inflammatory response to P. gingivalis.

Highlights

Porphyromonas gingivalis, a prominent component of the oral microbiome, is a Gram-negative anaerobe found in periodontal pockets of people with gum disease where it plays a major role in the pathogenesis of periodontitis, a chronic inflammatory disease that is a primary cause of adult tooth loss [1] [2] [3] [4]
Our findings revealed that stimulation of the acinar cells with the LPS leads to protein kinase Cδ (PKCδ)-mediated phosphorylation of spleen tyrosine kinase (Syk) on Ser which results in its localization with the membrane associated Toll-like receptor-4 (TLR4) complex and the activation through phosphorylation on Tyr
Taking into account emerging evidence as to the role of Syk in the modulation of bacterial endotoxin inflammatory signals associated with TLR4 activation and the secretion of various inflammatory mediators, including PGE2 and NO [18] [19], we investigated the nature of factors involved in the recruitment and interaction of Syk with TLR4 in sublingual salivary gland acinar cells in response to LPS of periodontopathic bacterium, P. gingivalis

Summary

Introduction

Porphyromonas gingivalis, a prominent component of the oral microbiome, is a Gram-negative anaerobe found in periodontal pockets of people with gum disease where it plays a major role in the pathogenesis of periodontitis, a chronic inflammatory disease that is a primary cause of adult tooth loss [1] [2] [3] [4]. Studies indicate that P. gingivalis LPS, like LPS of other Gram-negative bacteria [9], is a potent activator of TLR4 leading to its dimerization at the several critical Tyr residues that are essential for the initiation of downstream signaling events [6]. The activated MAPKs, including extracellular signal-regulated kinase (ERK), c-Jun terminal kinase (JNK), and p38 [10] [11], along with IKK, in turn, exert their control over transcription factors implicated in the induction of the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes that lead to up-regulation in the production of inflammatory mediators, PGE2 and NO [11] [12] [13]

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Conclusion