Biological effects of interleukin‐6 on Gingival Fibroblasts: Cytokine regulation in periodontitis

Abstract

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.

IL‑18 promotes the secretion of matrix metalloproteinases in human periodontal ligament fibroblasts by activating NF‑κB signaling

“…Periodontitis is a chronic infectious disease caused by microorganisms in dental plaque and is characterized by the progressive destruction of periodontal tissues (23). The endotoxins of periodontal-specific pathogens, including Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemura, can cause a large number of inflammatory cytokines to be released in the local and peripheral blood system (24).…”

Aminothiazoles inhibit osteoclastogenesis and PGE2 production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs

“…Another study by Tominari et al showed that osteoclast differentiation from RANKL‐stimulated mouse bone marrow macrophages is suppressed by compounds inhibiting PGE 2 synthesis by targeting both COX‐2 and mPGES‐1. Both RANKL‐RANK and LPS‐TLR4 signalling pathways are mediated via transcription factor NF‐κB. In response to stimuli, the IKKα/IKKβ/NEMO (IKKs) complex is activated, leading to dissociation of IκBα/NF‐κB complex, and subsequently to nuclear translocation of NF‐κB .…”

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

“…A recent report has shown that IL-1β-expressed inflammatory macrophages produce amyloid β (the main component of the hall marker in the brain of AD patients) in the gingival tissues of the patients with periodontitis as well as in the liver of mice after chronic systemic P. gingivalis infection, indicating that inflammatory macrophages in periodontitis may contribute to neurodegenerative diseases such as AD [34]. IL-6 triggers the generation of vascular endothelial growth factor (VEGF) and MMP-1, making great contribution to the development of periodontitis [35] and synergic effects of IL-1β and IL-6 upregulate MMPs, Evidence-Based Complementary and Alternative Medicine contributing to the tissue destruction in periodontitis by collagen degradation and bone resorption [36]. It is noted that chemical ablation of macrophages in mice prevents the P. gingivalis-induced alveolar bone resorption, demonstrating important roles for macrophages during periodontitis [37].…”