Clinical significance of GCF sIL-6R and calprotectin to evaluate the periodontal inflammation

Kajiura, Yukari; Lew, Jung Hwan; Ikuta, Takahisa; Nishikawa, Yasufumi; Kido, Jun‐ichi; Nagata, Toshihiko; Naruishi, Koji

doi:10.1177/0004563216680232

Cited by 18 publications

(26 citation statements)

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“…The present study demonstrated that calprotectin amounts and concentrations in PICF samples were significantly higher from diseased sites than from healthy sites, and a positive association was observed between calprotectin levels and clinical indicators such as PD and GI scores. This result for peri-implant diseases was similar to previous findings obtained in diagnostic studies on periodontal diseases [ 16 , 33 ]. A significant difference was noted in calprotectin amounts between GI-0 group and GI-1 or GI-2 group, suggesting that PICF calprotectin indicates initial, weak inflammation in peri-implant diseases because calprotectin is mainly existed in leukocytes that more express at early stage of inflammation and acute inflammation [ 14 , 15 ].…”

Section: Discussionsupporting

confidence: 91%

Calprotectin and cross-linked N-telopeptides of type I collagen levels in crevicular fluid from implant sites with peri-implant diseases: a pilot study

et al. 2018

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BackgroundPeri-implant crevicular fluid (PICF) contains calprotectin and NTx, which are markers for inflammation and bone resorption, respectively. The aims of this pilot study were to compare calprotectin and NTx levels in PICF from implant sites with or without peri-implant diseases and to evaluate the usefulness of calprotectin and NTx as diagnostic markers for peri-implant diseases.MethodsThirty-five patients with dental implants participated in this pilot study. PICF samples were collected from peri-implant disease sites (n = 40) and non-diseased (healthy) sites (n = 34) after clinical indicators including probing depth (PD), bleeding on probing (BOP), gingival index (GI), and bone loss (BL) rate were investigated. Calprotectin and NTx amounts in PICF were measured using their respective ELISA kits and then compared between diseased and healthy samples. The relationship between PICF calprotectin or NTx levels and clinical indicator levels was investigated. A receiver operating characteristic (ROC) curve analysis of calprotectin and NTx was performed to predict peri-implant diseases.ResultsCalprotectin and NTx levels in PICF were significantly higher from peri-implant disease sites than from healthy sites. PICF calprotectin amounts correlated with PD, and its levels were significantly higher in the GI-1 and GI-2 groups than in the GI-0 group. PICF NTx amounts correlated with PD and the BL rate. ROC curves indicated that PICF calprotectin and NTx are useful biomarkers for peri-implant diseases.ConclusionsCalprotectin and NTx in PICF have potential as biomarkers for the diagnosis of peri-implant diseases.

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Section: Discussionsupporting

confidence: 91%

Calprotectin and cross-linked N-telopeptides of type I collagen levels in crevicular fluid from implant sites with peri-implant diseases: a pilot study

et al. 2018

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“…Furthermore, we showed previously that IL-6 binding to HGFs increases significantly in the presence of sIL-6R [20]. Considering the possible source of sIL-6R in periodontitis lesions, we reported that sIL-6R production was induced by IL-6 and CPT in THP-1 macrophages [7,21]. Importantly, we showed that CPT-mediated induction of sIL-6R inhibited significantly in THP-1 macrophages by TACE specific inhibitor, TAPI-1 (Fig.…”

Section: Discussionmentioning

confidence: 51%

“…A soluble form of interleukin 6 receptor (sIL-6R), known as an IL-6 agonist, is released by proteolytic cleavage from cell surface of immune/inflammatory cells such as lymphocytes and macrophages [6]. Our recent findings showed that sIL-6R levels in gingival crevicular fluid (GCF) of inflamed sites are significantly higher than in the healthy sites in periodontitis patients [7]. Importantly, it has been reported that both IL-1β and IL-6 levels in GCF were significantly elevated in diabetic patients [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, sIL-6R is an essential molecule for IL-6 signaling in HGFs. In addition, significant elevation of calprotectin (CPT), a heterodimer of S100A8 and S100A9, are found in inflamed periodontal tissues [7]. Our previous findings showed that CPT induces not only IL-6 production in HGFs [12], but also sIL-6R production in THP-1 macrophages [7], resulting in progression of periodontitis by induction of IL-6 cascades.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, significant elevation of calprotectin (CPT), a heterodimer of S100A8 and S100A9, are found in inflamed periodontal tissues [7]. Our previous findings showed that CPT induces not only IL-6 production in HGFs [12], but also sIL-6R production in THP-1 macrophages [7], resulting in progression of periodontitis by induction of IL-6 cascades. Furthermore, vascular endotherial growth factor (VEGF) is a significant factor for diabetic complications, and is implicated in the development of neovascularization and endotherial dysfunction in diabetic retinopathy [13].…”

Section: Introductionmentioning

confidence: 99%

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High Glucose-Mediated Cytokine Regulation in Gingival Fibroblasts and THP-1 Macrophage: a Possible Mechanism of Severe Periodontitis with Diabetes

Lew

Naruishi

Kajiura

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic patients are susceptible to severe periodontitis, but the precise mechanism is not fully understood. Aim of this study was to explore the biological pathogenesis of severe periodontitis in diabetic patients focusing on the crosstalk of human gingival fibroblasts (HGFs) and macrophages. Methods: A total of 70 periodontitis patients with or without diabetes mellitus (DM) were enrolled, and the statistical relationships of diabetic conditions to the periodontal inflammatory parameters were examined by cross-sectional study. In in vitro study, HGFs cell line CRL-2014® (ATCC) and differentiated THP-1 macrophages were cultured with normal glucose (NG: 5.5 mM) or high glucose (HG: 25 mM) condition, and treated with indicated inflammatory factors such as calprotectin (CPT), interleukin (IL)-1β and IL-6. To examine the effects of HG on soluble IL-6 receptor (sIL-6R) production in THP-1 macrophages, the supernatants were collected and the sIL-6R levels were measured by ELISA. To examine the effects of HG on IL-1β or IL-6-induced matrix metalloproteinase (MMPs) production in HGFs, the supernatants were collected. Levels of MMP-1 and tissue inhibitor of MMP-1 (TIMP-1) were measured by ELISA. Finally, after conditioned medium (CM) from THP-1 macrophages cultured with NG or HG conditions was collected, HGFs were treated with the CM. The supernatants were collected 24 hours later and the levels of MMP-1 and TIMP-1 were measured. To examine the specific effects of IL-1β contained in CM on MMP-1 and TIMP-1 production in HGFs, IL-1 receptor antagonist (IL-1ra) was used. Results: There were statistical correlation between IL-1β and sIL-6R levels in gingival crevicular fluid (GCF) and HbA1c in periodontitis patients with DM (IL-1β: P=0.035, sIL-6R: P=0.040). HG and CPT significantly induced sIL-6R production in THP-1 macrophages. HG significantly enhanced IL-1β or IL-6/sIL-6R-induced MMP-1 production in HGFs. The increase of MMP-1 by both IL-1β and IL-6/sIL-6R was significantly inhibited by specific ERK or IκB inhibitors. Corresponding to the regulation of MMP-1 production, HG condition increased the phosphorylation of p44/42 MAPK and IκBα in HGFs treated with IL-1β or IL-6/sIL-6R. Finally, MMP-1 production in HGFs cultured with HG increased significantly by CM from THP-1 macrophages cultured with HG. The induction of MMP-1 by the CM from THP-1 macrophages cultured with HG was significantly inhibited by dose dependent of IL-1ra in HGFs cultured with HG. Conclusion: Diabetic conditions such as HG induce IL-1β and sIL-6R production from macrophages in inflammatory periodontal tissues and may exacerbate the periodontitis synergistically via MMP-1 production from HGFs.

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

Naruishi

Nagata

2018

Journal Cellular Physiology

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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.

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Clinical significance of GCF sIL-6R and calprotectin to evaluate the periodontal inflammation

Cited by 18 publications

References 26 publications

Calprotectin and cross-linked N-telopeptides of type I collagen levels in crevicular fluid from implant sites with peri-implant diseases: a pilot study

Calprotectin and cross-linked N-telopeptides of type I collagen levels in crevicular fluid from implant sites with peri-implant diseases: a pilot study

High Glucose-Mediated Cytokine Regulation in Gingival Fibroblasts and THP-1 Macrophage: a Possible Mechanism of Severe Periodontitis with Diabetes

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

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