Abstract
Oral mucosal inflammatory responses to P. gingivalis and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in proinflammatory cytokine production, up-regu- lation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report that stimulation of salivary gland acinar cells with P. gingivalis LPS leads to p38 MAPK-dependent release of soluble TGF-α ligand and the increase in EGFR phosphorylation. Further, we show that the LPS-induced TGF-α shedding and EGFR transactivation involve the activation of membrane-associated metalloprotease, TACE also known as ADAM17, through phosphorylation by p38 MAPK, and require Rac1 participation. Moreover, we demonstrate that blocking the Rac1 activation leads to the suppression in the membrane translocation of Rac1 as well as p38, thus indicating that the LPS-elicited p38 membrane recruitment for TACE phosphorylation requires colocalization with Rac1. Hence, our findings imply that Rac1 membrane translocation serves as an essential platform for the localization of p38 with TACE, TGF-α ectodomain shedding, and the EGFR activation.
Highlights
Lipopolysaccharide (LPS), a component of the outer membrane of P. gingivalis bacterium colonizing the oral cavity, is recognized as a potent endotoxin responsible for eliciting persistent mucosal inflammation that leads to periodontal lesions and progressive destruction of teeth-supporting tissue, including bone loss [1]-[4]
Taking into account recent evidence as to the role of LPS in pro-inflammatory stimulus propagation through the processes associated with epidermal growth factor receptor (EGFR) transactivation [12] [15] [16], we investigated the factors involved in the release of EGFR ligand, transforming growth factor-α (TGF-α), by salivary gland acinar cells in response to LPS of periodontopathic bacterium, P. gingivalis
As recent literature evidence has linked the course of TACE induction to LPSelicited mitogen-activated protein kinase (MAPK) phosphorylation and Rac GTPase activation [12] [21], in the present study we investigated the nature of factors involved in P. gingivalis LPS-induced EGFR transactivation in salivary gland acinar cells
Summary
Lipopolysaccharide (LPS), a component of the outer membrane of P. gingivalis bacterium colonizing the oral cavity, is recognized as a potent endotoxin responsible for eliciting persistent mucosal inflammation that leads to periodontal lesions and progressive destruction of teeth-supporting tissue, including bone loss [1]-[4]. Studies indicate that in addition to its cognate epidermal growth factor (EGF) ligand, the EGFR activation occurs in response to transforming growth factor-α (TGF-α), heparin binding EGF-like growth factor (HB-EGF), epiregulin, amphiregulin, and epigen [18] [20]. All these ligands are expressed as inactive membrane-anchored proteins that in response to a specific cellular stimulus undergo proteolytic cleavage, termed ectodomain shedding, to release the particular mature growth factor [18] [21]
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