Porphyromonas gingivalis lipopolysaccharide-induced up-regulation in endothelin-1 interferes with salivary mucin synthesis via epidermal growth factor receptor transactivation.
Endothelin-I (ET-1) is a 21 amino acid peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1) that acts through G protein-coupled ETA and ETB receptors. Using mucous cells of sublingual salivary gland, we show that P. gingivalis lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis is accompanied by a marked increase in ET-I generation and the enhancement in ECE-1 activity. Inhibition of ECE-I with phosphoramidon led to the impedance of the LPS-induced ET-1 generation as well as countered the detrimental effect of the LPS on mucin synthesis. Moreover, the LPS inhibitory effect of on mucin synthesis was blocked by ETA receptor antagonist, BQ610, but not by ETB receptor antagonist, BQ788. The LPS-induced reduction in mucin synthesis, furthermore, was countered by PD153035 (76.8%), a specific inhibitor of EGFR kinase as well as PP2 (54.7%), a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation. Our findings are the first to demonstrate that P. gingivalis LPS detrimental effect on salivary mucin synthesis is intimately linked to the events controlled by EGFR transactivation, triggered by upregulation in ECE-1,enhancement in ET-1 production, and G protein-coupled ETA receptor activation.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D016966:Porphyromonas gingivalis / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D012463:Saliva / Q000378:metabolism*; D012469:Salivary Glands / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014343:Trypan Blue / Q000494:pharmacology; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
C412373:AG 1879; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009077:Mucins; D009842:Oligopeptides; D011743:Pyrimidines; D011799:Quinazolines; C087220:BQ 610; D066246:ErbB Receptors; D019061:src-Family Kinases; D014343:Trypan Blue; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline