Receptor for Advanced Glycation End Products is Required for HMGB1/S100A4/NF-κβ Interaction In Porphyromonas gingivalis Induced Gingival Inflammation

High-mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) are thought to play key roles in the progression of chronic inflammatory diseases. We recently showed that HMGB1 and RAGE might be involved in the progression of human gingival inflammation as novel inflammatory mediators. The molecular mechanisms governing the ability of RAGE to induce ligand-specific responses in gingival inflammation are still unknown. We identified HMGB1/S100A4/NF-κβ pathway, a global regulator of inflammation, as a major RAGE-responsive molecule induced by Porphyromonas gingivalis (P. gingivalis) in rat gingiva. Consistent with the observation that RAGE can be activated by multiple ligands, the elevated expression of RAGE-mediated HMGB1 and S100A4 expression in gingival inflammation. Phosphorylation of NF-κβ and IL-1β immunoreactivity was stronger in P. gingivalis challenged gingiva compared to the control. Quantitative real-time RT-PCR confirmed the increased expression of HMGB1, RAGE, and IL-1β mRNA in P. gingivalis challenged gingiva. Our results indicate that RAGE is a major target gene shared by HMGB1 and S100A4 and the coordinated action of RAGE and NF-κβ leads to the induction of gingival inflammation.