Platelet-activating factor mediates Porphyromonas gingivalis lipopolysaccharide interference with salivary mucin synthesis via phosphatidylinositol 3-kinase-dependent constitutive nitric-oxide synthase activation.
Platelet -activating factor (PAF), a phospholipid-derived messenger molecule, is now recognized as the most proximal mediator of cellular events triggered by bacterial lipopolysaccharide (LPS) stimulation. In this study, we assessed the role of PAF in the disturbances in salivary mucin synthesis evoked by LPS of periodontopathic bacterium, P. gingivalis. Using primary culture of mucous acinar cells of sublingual salivary gland, we show that a specific PAF antagonist, BN52020, prevents in a dose-dependent fashion (up to 83.7%) the LPS-induced reduction in mucin synthesis, and the effect is reflected in a marked decrease in the LPS-induced apoptosis (74.8%), NO generation (82.6%), and the expression of TNF-alpha (76.1%). The impedance by BN52020 of the LPS inhibitory effect on mucin synthesis was blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), which also obviated the inhibitory effect of BN52020 on the LPS-induced upregulation in apoptosis, TNF-alpha, and NO. A potentiation in the impedance by BN52020 of the LPS detrimental effect on mucin synthesis was however attained with NOS-2 inhibitor, 1400W, while cNOS inhibitor, L-NNA caused a reduction in the impedance effect of BN52020. However, while 1400W and BN52020 countered the potentiating effect of wortmannin on the LPS-induced decrease in mucin synthesis, a further exacerbation of the effect of wortmannin occurred in the presence of L-NNA. The findings implicate PAF as a pivotal factor affecting the extent of pathological consequences of P. gingivalis infection on salivary glands capacity for mucin production, and suggest that its release in response to the LPS serves as a negative regulator of PI3K controlling the pathway of cNOS activation.
Slomiany
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BL
Research Center University of Medicine and Dentistry of New Jersey, Newark, NJ 07103 - 2400, USA. slomiabr@umdnj.edu
Slomiany
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A
D000578:Amidines / Q000494:pharmacology; D000730:Androstadienes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001596:Benzylamines / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D046934:Ginkgolides; D005944:Glucosamine / Q000378:metabolism; D007783:Lactones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D009077:Mucins / Q000096:biosynthesis* / Q000737:chemistry; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D016966:Porphyromonas gingivalis / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012463:Saliva / Q000737:chemistry / Q000378:metabolism*; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D013361:Sublingual Gland / Q000166:cytology / Q000378:metabolism; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D015854:Up-Regulation; D000077191:Wortmannin; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000578:Amidines; D000730:Androstadienes; D001596:Benzylamines; D046934:Ginkgolides; D005944:Glucosamine; D007783:Lactones; D008070:Lipopolysaccharides; D009077:Mucins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010972:Platelet Activating Factor; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; D019323:omega-N-Methylarginine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; C496316:Nos3 protein, rat; C477042:ginkgolide A