Efforts to understand the pathogenesis of periodontal diseases have been underway for decades. Studies of immunological aspects in addition to the structural components of gingival fibroblasts showed that the fibroblasts actively participate in immune and inflammatory events in periodontal diseases. Future strategies for the prevention and treatment of periodontal diseases should biologically regulate fibroblast activities. These cells are surrounded by monocyte-derived proinflammatory cytokines such as interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and lymphocyte-derived interleukin-6 (IL-6) in inflamed gingival tissue. Recent anti-cytokine therapy for inflammatory diseases including rheumatoid arthritis aimed to inhibit the binding of cytokines to targeted cells such as fibroblasts and condrocytes. IL-1beta and TNF-alpha are thought to be therapeutic targets because these cytokines are essential for the initiation of inflammatory immune reactions and are produced for prolonged periods in inflammatory diseases. IL-6 is also a target, because it is abundantly present in inflammatory lesions and activates fibroblasts in the presence of soluble IL-6 receptor. In addition, these cytokines accelerate gingival fibroblasts to produce collagenolytic enzymes, resulting in tissue destruction. Soluble receptors for IL-1beta and TNF-alpha are suggested to be candidates for therapeutic molecules, but soluble receptor for IL-6 is suggested to be a factor-stimulating fibroblast. This paper will review the utilization of soluble receptors specific to inflammatory cytokines which potentially stimulate fibroblasts to regulate biological events involved in the pathogenesis of periodontal diseases.

Chronic periodontitis is a silent infectious disease prevalent worldwide and affects lifestyle-related diseases. Therefore, efficient screening of patients is essential for general health. This study was performed to evaluate prospectively the diagnostic utility of a blood IgG antibody titer test against periodontal pathogens. Oral examination was performed, and IgG titers against periodontal pathogens were measured by ELISA in 1,387 individuals. The cut-off value of the IgG titer was determined in receiver operating characteristic curve analysis, and changes in periodontal clinical parameters and IgG titers by periodontal treatment were evaluated. The relationships between IgG titers and severity of periodontitis were analyzed. The best cut-off value of IgG titer against Porphyromonas gingivalis for screening periodontitis was 1.682. Both clinical parameters and IgG titers decreased significantly under periodontal treatment. IgG titers of periodontitis patients were significantly higher than those of healthy controls, especially in those with sites of probing pocket depth over 4 mm. Multiplied cut-off values were useful to select patients with severe periodontitis. A blood IgG antibody titer test for Porphyromonas gingivalis is useful to screen hitherto chronic periodontitis patients.

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Periodontitis is a bacterial infectious disease, and many inflammatory cytokines regulate periodontitis pathophysiology through a crosstalk between tissue cells and immune cells. Interleukin (IL)-6 is an important cytokine involved in the regulation of host response to bacterial infection. Human Gingival Fibroblasts (HGFs) are the most abundant cells in gingival connective tissues. Various HGF responses to periodontal pathogens or inflammatory cytokines contribute to the development of periodontitis. Lipopolysaccharide derived from Porphyromonas gingivalis (Pg LPS) and IL-1β significantly increase IL-6 production in HGFs. However, IL-6 cannot function in HGFs without the soluble form of the IL-6 receptor (sIL-6R), because HGFs do not express sufficient cell surface IL-6R to bind appreciable levels of IL-6. Importantly, sIL-6R is essential for IL-6 signaling in HGFs, and the sIL-6R is produced by differentiated THP-1 cells treated with IL-6. Calprotectin, a heterodimer of S100A8 and S100A9, is released during inflammation and significantly induces IL-6 production in HGFs via toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signals. Calprotectin also induces sIL-6R production in differentiated THP-1 cells. IL-6 induces vascular endothelial growth factor (VEGF), matrix-metalloproteinase-1 (MMP-1), and cathepsin L production in HGFs in the presence of sIL-6R. Taken together, calprotectin-induced IL-6 production in HGFs may cause periodontitis progression through a crosstalk of fibroblasts and macrophages. There are many reports that examine how cytokines are released from HGFs to cause beneficial or harmful effects in inflamed periodontal lesions. This review explores the pathophysiology of periodontitis by focusing IL-6-mediated crosstalk of HGFs and macrophages.