Toll-like receptor 4-dependent recognition of structurally different forms of chemically synthesized lipid As of Porphyromonas gingivalis

Abstract

SummaryPorphyromonas gingivalis is a Gram-negative anaerobic oral black-pigmented bacterium closely associated with chronic periodontitis. Lipopolysaccharide (LPS) derived from P. gingivalis is shown to be unusual because the LPS contains a greater number of lipid A species, such as tri-, tetra-, and/or pentaacylated lipid As. In this study, a lipid A possessing penta-fatty acyl chains derived from P. gingivalis strain 381 (compound PG-381-5FA) was synthesized, and examined for its immunobiological activities, compared with a tri-acylated lipid A (compound PG-381-3FA) synthesized previously. Compound PG-381-5FA, similar to compound PG-381-3FA, demonstrated weaker activity in a Limulus test as compared with Escherichia coli-type synthetic lipid A (compound 506). Compound PG-381-5FA, followed by compound PG-381-3FA, induced KC, interleukin-6, and tumour necrosis factor-a production in peritoneal macrophages from LPS-responsive C3H/HeN mice, but not in those from LPS-hyporesponsive C3H/HeJ mice. Furthermore, compound PG-381-5FA, as well as compound PG-381-3FA, activated nuclear factor-kB via Toll-like receptor (TLR)4/mD-2, but not TLR2, in a manner similar to compound 506, and worked as an antagonist for compound 506-induced cell activation. In the case of human peripheral blood mononuclear cells, compound PG-381-5FA showed much stronger IL-6-inducing activity than compound PG-381-3FA. The present results demonstrate that the chemical synthesis of a penta-acylated lipid A, mimicking the natural lipid A portion of LPS from P. gingivalis, is attributable to immune cell activation through TLR4, similar to that of compound 506.

Components of Host Response to Pathogenic Bacteria in Gingivitis

“…These results support the concept that pathogens evolved to manipulate innate immunity for promoting their adaptive fitness and, consequently, their capacity to cause disease (Finlay & McFadden 2006). The chemical and biological properties of P. gingivalis LPS and its lipid A are different from those of enterobacterial LPS and their lipid A (Ogawa 1994), and different forms of P. gingivalis lipid functionally interact with only TLR4 (Sawada et al 2007). Milward et al (Milward et al 2007) demonstrated that Fusobacterium nucleatum and Porphyromonas gingivalis have differential effects at the molecular level on oral epithelial cells and that their differences in activating NF-B nuclear translocation in oral epithelial cells may at least in part be responsible for the change in dynamics and kinetics of downstream gene expression.…”

Adsorption of Components of the Plasma Kinin-Forming System on the Surface ofPorphyromonas gingivalisInvolves Gingipains as the Major Docking Platforms

“…5B). The lack of interaction is most likely due to significant differences in the structures of LPSs derived from P. gingivalis and E. coli (41,57,76). Again, unequivocal binding was noted mainly for PK, but only at half the capacity observed for FimA.…”

Porphyromonas gingivalis Outer Membrane Vesicles Induce Selective Tumor Necrosis Factor Tolerance in a Toll-Like Receptor 4- and mTOR-Dependent Manner

“…In addition, dephosphorylation of lipid A by P. gingivalis phosphatases prevents TLR4 activation and promotes resistance to cationic antimicrobial peptides (48). Other reports, however, describe P. gingivalis LPS preparations as a highly heterogeneous mixture of different types of lipid A species with differential levels of stimulatory potency in their effects on TLR2 and TLR4 (10,14,49). In addition, a few studies demonstrated that TLR2 activity can be attributed to P. gingivalis lipoproteins (50)(51)(52).…”