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Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis. [ABSTRACT FROM AUTHOR]

Oxytocin (OX) is a posterior pituitary hormone secreted into the blood from axon terminals projecting from the posterior pituitary. Recent reports indicate OX plays an important role in the progression of inflammatory diseases such as rheumatoid arthritis. Pulpitis is caused by the activation of the biological defense mechanism of the dental pulp against cariogenic bacteria. However, the role of OX in the pathogenesis of pulpitis remains unknown. The aim of this study was to examine the effect of OX on CXC chemokine ligand 10 (CXCL10) production in human dental pulp stem cells (HDPSCs). Expression of the oxytocin receptor (OXR) on HDPSCs was detected by Western blot analysis and immunofluorescence. CXCL10 production in HDPSCs was measured using an enzyme‐linked immunosorbent assay kit. Western blot analysis was performed to determine the phosphorylation levels of signal transduction molecules, including nuclear factor kappa B, mitogen‐activated protein kinases (MAPKs), and Akt in HDPSCs. HDPSCs expressed OXR. OX significantly decreased CXCL10 production in tumor necrosis factor (TNF)‐α‐stimulated HDPSCs. The p38 MAPK and Akt pathways were related to the OX‐suppressed CXCL10 production in TNF‐α‐stimulated HDPSCs. These results indicate that OX appears to modulate the immune response in pulpitis via suppression of CXCL10 production by HDPSCs. [ABSTRACT FROM AUTHOR]

Effects of the antiosteoblastogenesis factor Semaphorin 4D (Sema4D), expressed by thrombin-activated platelets (TPs), on osteoblastogenesis, as well as osteoclastogenesis, were investigated in vitro. Intact platelets released both Sema4D and IGF-1. However, in response to stimulation with thrombin, platelets upregulated the release of Sema4D, but not IGF-1. Anti-Sema4D-neutralizing monoclonal antibody (mAb) upregulated TP-mediated osteoblastogenesis in MC3T3-E1 osteoblast precursors. MC3T3-E1 cells exposed to TPs induced phosphorylation of Akt and ERK further upregulated by the addition of anti-sema4D-mAb, suggesting the suppressive effects of TP-expressing Sema4D on osteoblastogenesis. On the other hand, TPs promoted RANKL-mediated osteoclastogenesis in the primary culture of bone-marrow-derived mononuclear cells (BMMCs). Among the known three receptors of Sema4D, including Plexin B1, Plexin B2 and CD72, little Plexin B2 was detected, and no Plexin B1 was detected, but a high level of CD72 mRNA was detected in RANKL-stimulated BMMCs by qPCR. Both anti-Sema4D-mAb and anti-CD72-mAb suppressed RANKL-induced osteoclast formation and bone resorptive activity, suggesting that Sema4D released by TPs promotes osteoclastogenesis via ligation to a CD72 receptor. This study demonstrated that Sema4D released by TPs suppresses osteogenic activity and promotes osteoclastogenesis, suggesting the novel property of platelets in bone-remodeling processes. [ABSTRACT FROM AUTHOR]

Human dental pulp cells (HDPCs) play an important role in pulpitis. Semaphorin3A (Sema3A), which is an axon guidance molecule, is a member of the secretory semaphorin family. Recently, Sema3A has been reported to be an osteoprotective factor and to be involved in the immune response. However, the role of Sema3A in dental pulp inflammation remains unknown. The aim of this study was to reveal the existence of Sema3A in human dental pulp tissue and the effect of Sema3A which is released from tumor necrosis factor (TNF)‐α‐stimulated HDPCs on production of proinflammatory cytokines, such as interleukin (IL)‐6 and CXC chemokine ligand 10 (CXCL10), from HDPCs stimulated with TNF‐α. Sema3A was detected in inflamed pulp as compared to normal pulp. HDPCs expressed Neuropilin‐1(Nrp1) which is Sema3A receptor. TNF‐α increased the levels of IL‐6 and CXCL10 in HDPCs in time‐dependent manner. Sema3A inhibited production of these two cytokines from TNF‐α‐stimulated HDPCs. TNF‐α induced soluble Sema3A production from HDPCs. Moreover, antibody‐based neutralization of Sema3A further promoted production of IL‐6 and CXCL10 from TNF‐α‐stimulated HDPCs. Sema3A inhibited nuclear factor (NF)‐κB P65 phosphorylation and inhibitor κBα degradation in TNF‐α‐stimulated HDPCs. These results indicated that Sema3A is induced in human dental pulp, and TNF‐α acts on HDPCs to produce Sema3A, which partially inhibits the increase in IL‐6 and CXCL10 production induced by TNF‐α, and that the inhibition leads to suppression of NF‐κB activation. Therefore, it is suggested that Sema3A may regulate inflammation in dental pulp and be novel antiinflammatory target molecule for pulpitis. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-35 is a novel anti-inflammatory cytokine that is produced by regulatory T cells. IL-35 is reported to suppress IL-17A-producing helper T (Th17) cell activation. IL-17A is related to progression of periodontitis. Furthermore, IL-35 and IL-17A are detected in human gingival crevicular fluid. However, the effect of IL-35 and interaction between IL-35 and IL-17A on pro-inflammatory cytokine production in human periodontal resident cells are still unclear. The aim of this study was to clarify the effect of IL-35 on IL-6 and IL-8 production in human periodontal ligament cells (HPDLCs) stimulated with IL-17A. IL-35 inhibited IL-6 and IL-8 production in IL-17A-stimulated HPDLCs. Moreover, western blot analysis showed that IL-35 suppressed extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-κB p65 phosphorylation in IL-17A-stimulated HPDLCs. Our findings suggested that IL-35 produced from regulatory T cells might inhibit progression of periodontitis by decreasing IL-17A-induced levels of IL-6 and IL-8. [ABSTRACT FROM AUTHOR]

Osteoclastogenesis was induced by RANKL stimulation in mouse monocytes to examine the possible bactericidal function of osteoclast precursors (OCp) and mature osteoclasts (OCm) relative to their production of NO and ROS. Tartrate-resistant acid phosphatase (TRAP)-positive OCp, but few or no OCm, phagocytized and killed Escherichia coli in association with the production of reactive oxygen species (ROS) and nitric oxide (NO). Phagocytosis of E. coli and production of ROS and NO were significantly lower in TRAP+ OCp derived from Toll-like receptor (TLR)-4 KO mice than that derived from wild-type (WT) or TLR 2 -KO mice. Interestingly, after phagocytosis, TRAP+ OCp derived from wild-type and TLR2-KO mice did not differentiate into OCm, even with continuous exposure to RANKL. In contrast, E. coli -phagocytized TRAP+ OCp from TLR4-KO mice could differentiate into OCm. Importantly, neither NO nor ROS produced by TRAP+ OCp appeared to be engaged in phagocytosis-induced suppression of osteoclastogenesis. These results suggested that TLR4 signaling not only induces ROS and NO production to kill phagocytized bacteria, but also interrupts OCm differentiation. Thus, it can be concluded that TRAP+ OCp, but not OCm, can mediate bactericidal activity via phagocytosis accompanied by the production of ROS and NO via TLR4-associated reprograming toward phagocytic cell type. [ABSTRACT FROM AUTHOR]

Shikonin, which is derived from Lithospermum erythrorhizon, a herb used in traditional medicine, has long been considered to be a useful treatment for various diseases in traditional oriental medicine. Shikonin has recently been reported to have several pharmacological properties, e.g., it has anti-microbial, anti-tumor, and anti-inflammatory effects. The aim of this study was to examine whether shikonin is able to influence the production of interleukin (IL)-6, IL-8, and/or chemokine C-C motif ligand (CCL)20, which contribute to the pathogenesis of periodontal disease, in human periodontal ligament cells (HPDLC). The production levels of IL-6, IL-8, and CCL20 in HPDLC were determined using an ELISA. Western blot analysis was used to detect nuclear factor kappa B (NF-κB) pathway activation in HPDLC. Shikonin prevented IL-1β- or tumor necrosis factor (TNF)-α-mediated IL-6, IL-8, and CCL20 production in HPDLC. Moreover, we found that shikonin suppressed the phosphorylation and degradation of inhibitor of kappa B-alpha (IκB-α) in IL-1β- or TNF-α-stimulated HPDLC. These findings suggest that shikonin could have direct beneficial effects against periodontal disease by reducing IL-6, IL-8, and CCL20 production in periodontal lesions. [ABSTRACT FROM AUTHOR]

Genipin, the aglycon of geniposide found in gardenia fruit has long been considered for treatment of inflammatory diseases in traditional oriental medicine. Genipin has recently been reported to have some pharmacological functions, such as antimicrobial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether genipin could modify matrix metalloproteinase (MMP)-1 and MMP-3, which are related to the destruction of periodontal tissues in periodontal lesion, expression in tumor necrosis factor (TNF)-α-stimulated human periodontal ligament cells (HPDLCs). Genipin prevented TNF-α-mediated MMP-1 and MMP-3 productions in HPDLCs. Moreover, genipin could suppress not only extracellular signal-regulated kinase (ERK) and Jun-N-terminal kinase (JNK) phosphorylations but also AMP-activated protein kinase (AMPK) phosphorylation in TNF-α-stimulated HPDLCs. Inhibitors of ERK and AMPK could inhibit both MMP-1 and MMP-3 productions. Moreover, we revealed the ERK inhibitor suppressed AMPK phosphorylation in TNF-α-stimulated HPDLCs. These data provide a new mechanism through which genipin could be used for the treatment of periodontal disease to prevent MMPs expression in periodontal lesion. [ABSTRACT FROM AUTHOR]

CC chemokine ligand 20 (CCL20) plays a central role in the recruitment of CCR6-expressing cells, including Th17 cells which are related to bone resorption in periodontal lesions and thus in the development of periodontal disease. IL-6 is an important cytokine that is associated with the pathogenesis of periodontitis. However, the effect of IL-6 on CCL20 production is uncertain. The aim of this study was to examine whether IL-6 could modify CCL20 expression in human periodontal ligament cells (HPDLCs). HPDLCs expressed gp130 but did not express IL-6R on the surface of HPDLCs. So, IL-6 trans-signaling is important to recognize IL-6 by HPDLCs. IL-6/sIL-6R stimulation enhanced CCL20 production in IL-1β-stimulated HPDLCs. IL-6 produced from IL-1β-stimulated HPDLCs with sIL-6R could increase CCL20 production in HPDLCs with sIL-6R. Signal transducer and activator of transcription (STAT)3 activation was related to CCL20 production in IL-1β and IL-6/sIL-6R-stimulated HPDLCs. Our data suggests that HPDLCs, in response to IL-6, sIL-6R, and IL-1β, may shift chemokine production to that favoring CCR6-expressing cells recruitment in periodontal lesions. [ABSTRACT FROM AUTHOR]

Background/Aims: Genipin, the aglycon of geniposide found in gardenia fruit has long been considered for treatment of various diseases in traditional oriental medicine. Genipin has been used as a blue colorant in food industry. Genipin has recently been reported to have some pharmacological functions, such as antimicrobial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether genipin could modify CCL20 and IL-6, which are related to bone resorption in periodontal disease, expression in human periodontal ligament cells (HPDLCs). Methods: CCL20 and IL-6 productions from HPDLCs were determined by ELISA. Western blot analysis was used for the detection of signal transduction molecules expressions in HPDLCs. Results: Genipin prevented IL-1β-mediated CCL20 and IL-6 production in HPDLCs. Moreover, genipin could suppress nuclear factor kappa B (NF-κB) p65, extracellular signalregulated kinase (ERK) and MAPK/ERK kinase (MEK) phosphorylations in IL-1β-stimulated HPDLCs. NF-κB inhibitor and ERK inhibitor significantly inhibited IL-6 and CCL20 productions from IL-1β-stimulated HPDLCs. Conclusions: These data provide a novel mechanism through which genipin could be used to provide direct benefits in periodontal disease to inhibit IL-6 and CCL20 productions in periodontal lesions. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development. [ABSTRACT FROM AUTHOR]

Interleukin-29 (IL-29) is a cytokine belonging to the Type III interferon family. It was recently detected in the gingival crevicular fluid of periodontitis patients. However, the role of IL-29 in the pathogenesis of periodontal disease remains unknown. The aim of this study was to examine the effects of IL-29 on C-X-C motif chemokine ligand 10 (CXCL10) production in human oral epithelial cells. We measured CXCL10 production in TR146 cells, which is a human oral epithelial cell line, using an enzyme-linked immunosorbent assay. We used a Western blot analysis to detect IL-29 receptor expression and the phosphorylation levels of signal transduction molecules, including p38 mitogen-activated protein kinases (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor (NF)- κB p65, in the TR146 cells. The TR146 cells expressed the IL-29 receptor. IL-29 induced CXCL10 production in the TR146 cells. IL-29 significantly enhanced CXCL10 production in tumor necrosis factor (TNF)-α-stimulated TR146 cells. The p38 MAPK, STAT3, and NF-κB pathways were found to be related to the IL-29-induced enhancement of CXCL10 production in TNF-α-stimulated TR146 cells. IL-29 promotes T helper 1-cell accumulation in periodontal lesions by inducing CXCL10 production in oral epithelial cells. [ABSTRACT FROM AUTHOR]

Gomisin N, which is a lignan isolated from Schisandra chinensis, has some pharmacological effects. However, the anti-inflammatory effects of gomisin N on periodontal disease are uncertain. The aim of this study was to examine the effect of gomisin N on inflammatory mediator production in tumor necrosis factor (TNF)-α-stimulated human periodontal ligament cells (HPDLC). Gomisin N inhibited interleukin (IL)-6, IL-8, CC chemokine ligand (CCL) 2, and CCL20 production in TNF-α-stimulated HPDLC in a dose-dependent manner. Moreover, we revealed that gomisin N could suppress extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK) phosphorylation in TNF-α-stimulated HPDLC though protein kinase B (Akt) phosphorylation was not suppressed by gomisin N treatment. In summary, gomisin N might exert anti-inflammatory effects by attenuating cytokine production in periodontal ligament cells via inhibiting the TNF-α-stimulated ERK and JNK pathways activation. [ABSTRACT FROM AUTHOR]

Alkannin, which is found in Alkanna tinctoria, a member of the borage family, is used as a food coloring. Alkannin has recently been reported to have certain biological functions, such as anti-microbial and anti-oxidant effects. It is known that CC chemokine receptor (CCR) 5-positive leukocytes contribute to alveolar bone resorption in periodontal lesions. The aim of this study was to examine whether alkannin inhibits the production of CC chemokine ligand (CCL) 3 and CCL5, which are CCR5 ligands, in human periodontal ligament cells (HPDLC). Interleukin (IL)-1β induced CCL3 and CCL5 production in HPDLC. Alkannin inhibited IL-1β-mediated CCL3 and CCL5 production in HPDLC in a dose-dependent manner. Moreover, we revealed that alkannin suppressed inhibitor of kappa B-α degradation in IL-1β-stimulated HPDLC. In addition, a nuclear factor (NF)-κB inhibitor significantly inhibited CCL3 and CCL5 production in IL-1β-stimulated HPDLC. These results demonstrate that alkannin inhibits CCR5 ligand production in IL-1β-stimulated HPDLC by attenuating the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Melatonin is a hormone that is mainly secreted by the pineal gland and exhibits a wide spectrum of activities, including antioxidant functions. Melatonin has been detected in gingival crevicular fluid. However, the role of melatonin in periodontal tissue is still uncertain. The aim of this study was to examine the effects of melatonin on inflammatory mediator expression in human periodontal ligament cells (HPDLC). Interleukin (IL)-1β induced CXC chemokine ligand (CXCL)10, matrix metalloproteinase (MMP)-1, and tissue inhibitors of metalloproteinase (TIMP)-1 production in HPDLC. Melatonin decreased CXCL10 and MMP-1 production and increased TIMP-1 production in IL-1β-stimulated HPDLC. Western blot analysis showed that melatonin inhibited p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) phosphorylation, and IkB-α degradation and phosphorylation in IL-1β-stimulated HPDLC. These results suggest that melatonin might inhibit Th1 cell migration by reducing CXCL10 production. Moreover, melatonin might inhibit soft tissue destruction by decreasing MMP-1 production in periodontal lesions. [ABSTRACT FROM AUTHOR]

The field of vascular biology has advanced significantly with bioreactor systems, which have become essential tools for investigating the mechanisms of vascular inflammatory diseases such as atherosclerosis, vasculitis, and aneurysms. These bioreactors allow researchers to recreate specific vascular environments, providing a controlled setting for studying the effects of blood flow, mechanical stress, and biochemical factors on vascular tissues. Through these systems, researchers can explore how physical and chemical cues contribute to disease processes and cellular responses, enhancing our understanding of disease progression. Bioreactor studies have demonstrated that hemodynamic forces, particularly shear stress, influence endothelial cell behavior and play a role in vascular pathologies. For instance, in atherosclerosis, disturbed flow patterns are associated with endothelial dysfunction and plaque development. By simulating these conditions, bioreactors provide insight into the effects of mechanical forces on vascular wall biology, highlighting how altered flow can contribute to disease. Bioreactors also support studies on the impacts of pulsatile flow and circumferential stress, allowing a closer approximation of physiological environments. Beyond flow dynamics, these systems facilitate investigation into how vascular cells respond to biochemical signals, inflammatory markers, and therapeutic interventions. This integrated approach allows for a more complete picture of the factors involved in vascular disease. Recent advancements, such as vessel-on-a-chip models and artery-mimicking setups, extend the capabilities of bioreactors by enabling researchers to model a broader range of conditions relevant to human physiology. In vasculitis studies, bioreactors help explore immune interactions with endothelial cells, especially with stem cell-derived cells that replicate patient-specific responses. Bioreactors also play a role in vascular tissue engineering, particularly in assessing materials and scaffold-free designs that may reduce inflammation in vascular grafts. These efforts contribute to the ongoing search for more compatible graft materials, with the potential to improve outcomes in clinical applications. This review provides a comprehensive overview of bioreactor technologies applied in vascular inflammation research, examining their designs, applications, and contributions to disease modeling. Organized into sections on bioreactor configurations, flow dynamics, biochemical interactions, and tissue engineering applications, the review concludes by discussing recent innovations and highlighting directions for future research, underscoring the role of bioreactors in bridging laboratory studies with insights into vascular disease. [ABSTRACT FROM AUTHOR]

Background/Aims: IL-4 is a multifunctional cytokine that is related with the pathological conditions of periodontal disease. However, it is uncertain whether IL-4 could control T cells migration in periodontal lesions. The aim of this study was to examine the effects of IL-4 on CCL11, which is a Th2-type chemokine, and CCL20, which is related with Th17 cells migration, productions from human periodontal ligament cells (HPDLCs). Methods: CCL20 and CCL11 productions from HPDLCs were monitored by ELISA. Western blot analysis was performed to detect phosphorylations of signal transduction molecules in HPDLCs. Results: IL-1β could induce both CCL11 and CCL20 productions in HPDLCs. IL-4 enhanced CCL11 productions from IL-1β-stimulated HPDLCs, though IL-4 inhibited CCL20 production. Western blot analysis showed that protein kinase B (Akt) and signal transducer and activator of transcription (STAT)6 pathways were highly activated in IL-4/IL-1β-stimulated HPDLCs. Akt and STAT6 inhibitors decreased CCL11 production, but enhanced CCL20 production in HPDLCs stimulated with IL-4 and IL-1β. Conclusions: These results mean that IL-4 enhanced Th2 cells migration in periodontal lesion to induce CCL11 production from HPDLCs. On the other hand, IL-4 inhibits Th17 cells accumulation in periodontally diseased tissues to inhibit CCL20 production. Therefore, IL-4 is positively related with the pathogenesis of periodontal disease to control chemokine productions in periodontal lesions. © 2016 The Author(s) Published by S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Vitamin D has important roles on control of calcium and phosphate levels in the body. However, the role of vitamin D on the pathogenesis of periodontal disease is still uncertain. Therefore, we examined the effect of the hormonal form of vitamin D, calcitriol, on inflammatory responses of human periodontal ligament cells (HPDLC). We detected vitamin D receptor expression in non-stimulated HPDLC. Calcitriol inhibited interleukin (IL)-6, IL-8, CC chemokine ligand (CCL) 20, CXC chemokine ligand (CXCL) 10, and matrix metalloproteinase (MMP)-3 release from IL-1β-stimulated HPDLC. Tissue inhibitor of metalloproteinase (TIMP)-1 production did not change by calcitriol. Moreover, we found c-jun N-terminal kinase (JNK) phosphorylation and IκB-α degradation in IL-1β-stimulated HPDLC were inhibited by calcitriol, and JNK and nuclear factor (NF)-κB inhibitors could decrease IL-6, IL-8, CCL20, CXCL10, and MMP-3 productions in IL-1β-treated HPDLC. These findings suggest that vitamin D could modulate inflammatory response in periodontal tissues. [ABSTRACT FROM AUTHOR]

CC chemokine ligand 20 (CCL20) is involved in the recruitment of Th17 cells and thus in the exacerbation of periodontal disease, but the effect of simultaneous interleukin (IL)-22 and IL-1β stimulation on CCL20 production in human gingival fibroblasts (HGFs) is uncertain. In this study, we investigated the mechanisms of IL-1β- and/or IL-22-induced CCL20 production in HGFs. A single stimulation of IL-22 could not induce CCL20 production. On the other hand, IL-22 could increase CCL20 production from IL-1β-stimulated HGFs in a dose-dependent manner. C-Jun N terminal kinase (JNK) and inhibitor of nuclear factor κB (IκB)-α phosphorylation were increased in IL-1β- and IL-22-stimulated HGFs. An inhibitor of nuclear factor (NF)-κB decreased IL-1β- and IL-22-induced CCL20 production, though an inhibitor of JNK did not modulate CCL20 production. These data suggest that IL-1β in cooperation with IL-22 could increase Th17 cell accumulation in periodontally diseased tissues to enhance CCL20 production in HGFs. [ABSTRACT FROM AUTHOR]

Background: CC chemokine ligand 11 (CCL11) is related to Th2 cells migration via CC chemokine receptor 3 (CCR3). Th2 cells are involved in the etiology of periodontal disease. However, how the infiltration of Th2 cells is controlled in periodontally diseased tissues is unknown. (-)-Epigallocatechin gallate (EGCG), the major catechin in green tea, has multiple beneficial effects, but the effects of EGCG on CCL11 production are uncertain. In this study, we investigated whether cytokines could induce CCL11 production in human gingival fibroblasts (HGFs). Moreover, we examined the effects of EGCG on CCL11 production in HGFs. Methods and Results: ELISA analysis disclosed that interleukin (IL)-4 synergistically enhanced CCL11 production in IL-1β or tumor necrosis factor (TNF)-α-stimulated HGFs. EGCG prevented IL-1β/ IL-4 or TNF-α/IL-4-mediated CCL11 production in a concentration dependent manner. CCL11 production in HGFs was positively regulated by p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N terminal kinase (JNK). Western blot analysis revealed that EGCG treatment prevented IL-1β/IL-4 or TNF-α/IL-4-induced ERK and JNK activation in HGFs. Conclusions: These data provide that CCL11 production in HGFs could be associated with Th2 cells infiltration in periodontal lesions. Moreover, EGCG is useful for periodontitis treatment to inhibit CCL11 production. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Highlights: [•] TLR3 ligand induced CCL20 production from human gingival fibroblasts (HGFs). [•] TLR3 ligand synergistically enhanced CCL20 production from IL-1β-stimulated HGFs. [•] p38 MAPK, JNK and NF-κB activations are related with CCL20 production in HGFs. [ABSTRACT FROM AUTHOR]

Abstract: CC chemokine ligand 20 (CCL20) is related to T-helper (Th)-17 cell migration, and Th17 cells play important roles in exacerbation in periodontal disease. However, the effect of tumor necrosis factor–like weak inducer of apoptosis (TWEAK) on CCL20 production is unknown. In this study, we examined the mechanisms of TWEAK in combination with interleukin (IL)-1β-induced CCL20 production in human gingival fibroblasts (HGFs). TWEAK alone did not induce CCL20 production in HGFs. However, TWEAK enhanced CCL20 expression from IL-1β-stimulated HGFs in a dose-dependent manner. Inhibitors of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and nuclear factor κB (NF-κB) significantly inhibited CCL20 production in TWEAK and IL-1β-stimulated HGFs. Western blot analysis revealed that phosphorylations of ERK, Akt, and inhibitor of NF-κB were enhanced in TWEAK and IL-1β-treated HGFs. These data suggest that TWEAK is positively related to Th17 cell migration in periodontally diseased tissues to enhance CCL20 production in IL-1β-stimulated HGFs. [Copyright &y& Elsevier]

Abstract: CXC chemokine ligand 10 (CXCL10) plays an important role in the infiltration of Th1 cells and thus in the exacerbation of periodontal disease. Theaflavin-3,3′-digallate (TFDG), polyphenol in black tea, has some beneficial effects but the effect of TFDG on CXCL10 production from human gingival fibroblasts (HGFs) is uncertain. In this study, we investigated the mechanisms by which TFDG may inhibit oncostatin M (OSM)-induced CXCL10 production in human gingival fibroblasts. TFDG prevented OSM-mediated CXCL10 production by HGFs in a dose dependent manner. TFDG significantly inhibited OSM-induced phosphorylation of c-Jun N terminal kinase (JNK), protein kinase B (Akt) (Ser473) that are related to CXCL10 production from OSM-stimulated HGFs. In addition, TFDG suppressed OSM receptor (OSMR) β expression on HGFs. These data provide a novel mechanism where the black tea flavonoid, theaflavin, could provide direct benefits in periodontal disease. [Copyright &y& Elsevier]

It is well known that Semaphorin 4D (Sema4D) inhibits IGF-1-mediated osteogenesis by binding with PlexinB1 expressed on osteoblasts. However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-α and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-α and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption. [ABSTRACT FROM AUTHOR]