A drug development study for a periodontal disease : Biological properties of synthetic lipid A of Porphyromonas gingivalis lipopolysaccharide

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A pentaacyl and diphosphoryl lipid A molecule (J Bacteriol 1995: 177: 2098) found in the lipid A isolated from P. gingivalis LPS was chemically synthesized, and its characteristics were evaluated to reconfirm its interesting bioactivities including low endotoxicity and activity against LPS-unresponsive C3H/HeJ mouse cells. The synthesized P. gingivalis lipid A (synthetic Pg-LA) exhibited strong activities almost equivalent to those of Escherichia coli-type synthetic lipid A (compound 506) in all assays on LPS-responsive mice, and cells. LPS and native lipid A of P. gingivalis displayed overall endotoxic activities, but its potency was reduced in comparison to the synthetic analogs. In the assays using C3H/HeJ mouse cells, the LPS and native lipid A significantly stimulated splenocytes to cause mitosis, and peritoneal macrophages to induce TNF-D and IL-6 production. However, synthetic Pg-LA and compound 506 showed no activity on the LPS-unresponsive cells. Inhibition assays using some i … More nhibitors including anti-human TLR 2 and TLR4/MD-2 complex monoclonal antibodies showed that the biological activity of synthetic Pg-LA was mediated only through the TLR4 signaling pathway that might act as a receptor for LPS, whereas TLR2, possibly together with CD14, was associated with the signaling cascade for LPS and native lipid A of P. gingivalis, in addition to the TLR4 pathway. These results suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including the activity on C3H/HeJ mouse cells by TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having multiple lipid A moieties.In conclusion, these findings suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including the activity on C3H/HeJ mouse cells by TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having high heterogeneity in lipid A moiety. To elucidate these problems, we are now attempting to evaluate the biological characterizations of tetra-acylated monophosphorylated or diphosphorylated species with the predominant molecules found in P. gingivalis native lipid A, using each chemically synthesized analog. Less