シズイ サイボウ ノ シゼン メンエキ ハンノウ ニオケル IDO ユウドウ オ カイシタ IFN-γ ノ チョウセツテキ ヤクワリ

In the progression of pulpitis, marked infiltration of inflammatory cells such as activated T cells producing interferon-γ (IFN-γ) is observed. Indoleamine 2, 3-dioxygenase (IDO) is a regulator of immune responses and the IDO expression is induced by IFN-γ in a variety of cells, whose expression in dental pulp is unknown. Dental pulp cells have a capacity to produce various pro-inflammatory cytokines through microbial pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) or nucleotide-binding oligomerization domain (NOD) like receptors. We hypothesized that IFN-γ can modulate immune response to PRRs ligands on the dental pulp cells. The purpose of this study was to determine the role of IFN-γ in the innate immune response on production of pro-inflammatory cytokines such as C-X-C motif chemokine 10 (CXCL10) and interleukin (IL)-6 and IDO expression in cultured human dental pulp cells (HDPC). Enzyme-linked immunosorbent assay revealed that IFN-γ significantly up-regulated CXCL10 and IL-6 production in the HDPC stimulated with ligands for PRRs such as TLR2, TLR4, NOD1 and NOD2 in a concentration-dependent manner. Immunohistochemistry demonstrated expression of IDO in inflamed pulp tissue. In addition, IFN-γ in combination with the PRR ligands enhanced IDO expression in the HDPC compared with IFN-γ alone. Moreover, CXCL10 production in IFN-γ-stimulated HDPC was inhibited by an IDO inhibitor. Taken together, this study demonstrated the synergistic effects by IFN-γ on CXCL10 and IL-6 production and expression of IDO in HDPC. These findings suggest that IFN-γ may modulate the innate immune response of dental pulp cells

Caffeic Acid Phenethyl Ester Induces Vascular Endothelial Growth Factor Production and Inhibits CXCL10 Production in Human Dental Pulp Cells

The survival rate of root non-vital teeth is lower than that of vital teeth. Therefore, to preserve the dental pulp is very important. The vascular endothelial growth factor (VEGF) is the most potent angiogenic factor involved in the vitality of dental pulp including reparative dentin formation. Caffeic acid phenethyl ester (CAPE) is a physiologically active substance of propolis and has some bioactivities such as anti-inflammatory effects. However, there are no reports on the effects of CAPE on dental pulp inflammation. In this study, we investigated the effects of CAPE on VEGF and inflammatory cytokine production in human dental pulp cells (HDPCs) to apply CAPE to an ideal dental pulp protective agent. We found that CAPE induced VEGF production from HDPCs. Moreover, CAPE induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) in HDPCs. Furthermore, CAPE inhibited C-X-C motif chemokine ligand 10 (CXCL10) production in Pam3CSK4- and tumor necrosis factor-alpha (TNF-α)-stimulated HDPCs. In conclusion, these results suggest that CAPE might be useful as a novel biological material for vital pulp therapy by exerting the effects of VEGF production and anti-inflammatory activities

カフェイン酸フェネチルエステル（CAPE）がラット象牙芽細胞様細胞のVEGF発現と産生に与える影響

Caffeic acid phenethyl ester (CAPE), the main component of propolis, has various biological activities including anti-inflammatory effect and wound healing promotion. Odontoblasts located in the outermost layer of dental pulp play crucial roles such as production of growth factors and formation of hard tissue termed reparative dentin in host defense against dental caries. In this study, we investigated the effects of CAPE on the upregulation of vascular endothelial growth factor (VEGF) and calcification activities of odontoblasts, leading to development of novel therapy for dental pulp inflammation caused by dental caries. CAPE significantly induced mRNA expression and production of VEGF in rat clonal odontoblast-like KN-3 cells cultured in normal medium or osteogenic induction medium. CAPE treatment enhanced nuclear factor-kappa B (NF-κB) transcription factor activation, and furthermore, the specific inhibitor of NF-κB significantly reduced VEGF production. The expression of VEGF receptor- (VEGFR-) 2, not VEGFR-1, was up regulated in KN-3 cells treated with CAPE. In addition, VEGF significantly increased mineralization activity in KN-3 cells. These findings suggest that CAPE might be useful as a novel biological material for the dental pulp conservative therapy

Odontoblasts in dental pulp innate immunity

Odontoblasts located in the outermost layer of dental pulp form a natural barrier between mineralized tissues, dentin, and soft tissues, dental pulp, of the vital tooth, and they first recognize caries-related pathogens and sense external irritations. Therefore, odontoblasts possess a specialized innate immune system to fight oral pathogens invading into dentin. Generally, the rapid initial sensing of microbial pathogens, especially pathogen-associated molecular patterns (PAMPs) shared by microorganisms, are mediated by pattern recognition receptors (PRRs), such as Toll-like receptor and the nucleotide-binding oligomerization domain (NOD). The innate immune responses in odontoblasts initiated by sensing oral pathogens provide host protective events, such as inflammatory reactions, to produce a variety of pro-inflammatory mediators, including chemokines and cytokines. These attract various inflammatory cells and cause antibacterial reactions, such as the production of defensins, to kill microorganisms in the proximal region of the odontoblast layer. This review focuses on innate immunity, especially cellular and molecular mechanisms regarding the sensing of PAMPs from oral pathogens by PRRs, in odontoblasts and provides information for future studies for the development of novel therapeutic strategies, including diagnosis and treatment, to prevent exceeding dental pulp inflammation and preserve the dental pulp tissues

歯髄象牙芽細胞の自然免疫反応におけるNOD1の役割

Caries-related pathogens are first recognized by odontoblasts and induce inflammatory events that develop to pulpitis. Generally, initial sensing of microbial pathogens is mediated by pattern recognition receptors, such as Toll-like receptor and nucleotide-binding oligomerization domain (NOD); however, little is known about NODs in odontoblasts. In this study, the levels of NODs expressed in rat odontoblastic cell line, KN-3, were assessed by flow cytometry and the levels of chemokines in NOD-specific ligand-stimulated KN-3 cells were analyzed by real-time PCR and ELISA. The signal transduction pathway activated with NOD-specific ligand was assessed by blocking assay with specific inhibitors and reporter assay. In KN-3 cells, the expression level of NOD1 was stronger than that of NOD2 and the production of chemokines, such as CINC-1, CINC-2, CCL20, and MCP-1, was upregulated by stimulation with NOD1-specific ligand, but not with NOD2-specific ligand. CINC-2 and CCL20 production by stimulation with NOD1-specific ligand was reduced by p38 MAPK and AP-1 signaling inhibitors. Furthermore, the reporter assay demonstrated AP-1 activation in NOD1-specific ligand-stimulated KN-3 cells. These findings indicated that NOD1 expressed in odontoblasts functions to upregulate the chemokines expression via p38-AP-1 signaling pathway and suggested that NOD1 may play important roles in the initiation and progression of pulpitis

ノウソッチュウ カンジャ ノ コウクウナイ ショケン ト シカ カイニュウ ノ ユウヨウセイ ニツイテ

We analyzed the need for dental intervention in patients with acute cerebral vascular disorders. In this study, we enrolled 43 individuals in SCU (male: 28, female: 15) in need of oral health management. The mean age of the patients was 68.0 ± 14.9. They had been diagnosed as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, or transient ischemic attack. Thirteen subjects were affected with pneumonia and could not handle self-care management. Furthermore, 10 subjects had poor oral hygiene. There were clearly more pneumonia patients in the intubation group compared to the non-intubation group. In addition, 18 cases (41.9%) needed dental treatment, and 5 cases received dental treatment. Patients with acute stroke had poor oral hygiene with disturbance of consciousness and paralysis, suggesting a possible cause of pneumonia in these patients. Half of patients required dental intervention, indicating that oral management may be necessary for stroke patients to prevent the occurrence of pneumonia

トクシマ ダイガク ビョウイン ニオケル シュウジュツキ コウクウ キノウ カンリ ノ ゲンジョウ ト カダイ

It has been shown that oral hygiene affects the onset of perioperative complications. The usefulness of perioperative oral function management aiming at the outbreak decrease in treatment complications and an early discharge was recognized. As a result, perioperative oral function management fee was founded at revision of medical service fees in Fiscal year 2012. 　In this clinical study, we evaluated the implementation of perioperative oral function management in Tokushima University Hospital. We examined 781 patients, including 563 patients for surgery and 218 patients for chemotherapy and radiotherapy. The mean age of patients was 58.8 ± 12.4 years old. 　The implementation rate of perioperative oral function management was 9.7% in the patients of surgery, and 17.4% in those of chemotherapy and radiotherapy. The highly required medical department was neurosurgery in the patients of surgery, and hematology in those of chemotherapy and radiotherapy. The mean number of tooth present was 21.3 ± 7.1 in the patients of surgery, and 19.8 ± 7.2 in those chemotherapy and radiotherapy. The rate of dental treatment was required in 40.5% of total patients who received surgery, and in 51.4% of patients who received chemotherapy and radiotherapy. The rate of patients who received denture treatment attained to 11.9% of the whole patients receiving surgery, and 13.3% of patients receiving chemotherapy and radiotherapy. 　It was revealed that there were many patients required potential demands in perioperative oral function management, and that there were many patients who need dental or denture treatment. We would like to develop perioperative oral function management by the interprofessional collaboration in health and social care

Caffeic Acid Phenethyl Ester Induces Vascular Endothelial Growth Factor Production and Inhibits CXCL10 Production in Human Dental Pulp Cells

The survival rate of root non-vital teeth is lower than that of vital teeth. Therefore, to preserve the dental pulp is very important. The vascular endothelial growth factor (VEGF) is the most potent angiogenic factor involved in the vitality of dental pulp including reparative dentin formation. Caffeic acid phenethyl ester (CAPE) is a physiologically active substance of propolis and has some bioactivities such as anti-inflammatory effects. However, there are no reports on the effects of CAPE on dental pulp inflammation. In this study, we investigated the effects of CAPE on VEGF and inflammatory cytokine production in human dental pulp cells (HDPCs) to apply CAPE to an ideal dental pulp protective agent. We found that CAPE induced VEGF production from HDPCs. Moreover, CAPE induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) in HDPCs. Furthermore, CAPE inhibited C-X-C motif chemokine ligand 10 (CXCL10) production in Pam3CSK4- and tumor necrosis factor-alpha (TNF-α)-stimulated HDPCs. In conclusion, these results suggest that CAPE might be useful as a novel biological material for vital pulp therapy by exerting the effects of VEGF production and anti-inflammatory activities

The roles of odontoblasts in dental pulp innate immunity

Summary: Odontoblasts located in the outermost layer of dental pulp form a natural barrier between mineralized tissues, dentin, and soft tissues, dental pulp, of the vital tooth, and they first recognize caries-related pathogens and sense external irritations. Therefore, odontoblasts possess a specialized innate immune system to fight oral pathogens invading into dentin. Generally, the rapid initial sensing of microbial pathogens, especially pathogen-associated molecular patterns (PAMPs) shared by microorganisms, are mediated by pattern recognition receptors (PRRs), such as Toll-like receptor and the nucleotide-binding oligomerization domain (NOD). The innate immune responses in odontoblasts initiated by sensing oral pathogens provide host protective events, such as inflammatory reactions, to produce a variety of pro-inflammatory mediators, including chemokines and cytokines. These attract various inflammatory cells and cause antibacterial reactions, such as the production of defensins, to kill microorganisms in the proximal region of the odontoblast layer. This review focuses on innate immunity, especially cellular and molecular mechanisms regarding the sensing of PAMPs from oral pathogens by PRRs, in odontoblasts and provides information for future studies for the development of novel therapeutic strategies, including diagnosis and treatment, to prevent exceeding dental pulp inflammation and preserve the dental pulp tissues. Keywords: Odontoblast, Pattern recognition receptor, Pathogen-associated molecular pattern, Inflammation, Pro-inflammatory mediator, Damage-associated molecular patter