Nobiletin Decreases Inflammatory Mediator Expression in Tumor Necrosis Factor-Stimulated Human Periodontal Ligament Cells

Nobiletin, a biologically active substance in the skin of citrus fruits, has been reported to be an effective anti-inflammatory, anticancer, and antimicrobial agent. In this study, we aimed to examine the anti-inflammatory effects of nobiletin on tumor necrosis factor- (TNF-) stimulated human periodontal ligament cells (HPDLCs). Our results demonstrated that nobiletin treatment could decrease the expressions of inflammatory cytokines (C-X-C motif chemokine ligand (CXCL)10, C-C motif chemokine ligand (CCL)2, and interleukin- (IL-) 8), matrix metalloproteinases (MMPs) (MMP1 and MMP3), and prostaglandin-endoperoxide synthase 2 (PTGS2) in TNF-stimulated HPDLCs. Moreover, we revealed that nobiletin could inhibit the activation of nuclear factor- (NF-) κB and protein kinase B (AKT1) pathways in TNF-stimulated HPDLCs. Furthermore, nobiletin treatment enhanced nuclear factor, erythroid 2 like 2 (NFE2L2) and heme oxygenase 1 (HMOX1) expressions in TNF-stimulated HPDLCs. In conclusion, these findings suggest that nobiletin can inhibit inflammatory responses in TNF-stimulated HPDLCs by inhibiting NF-κB and AKT1 activations and upregulating the NFE2L2 and HMOX1 expression

TGF-β1 and IL-4 induce CCL11 production

Transforming growth factor (TGF)-β1 is a multifunctional cytokine, which can control certain functions of various kinds of cells. However, it is unclear whether TGF-β1 affects T-cell migration in periodontal lesions. The aim of this study was to examine the effects of TGF-β1 on the production of C-C chemokine ligand (CCL)11, which is a T-helper 2-type chemokine, in human periodontal ligament cells (HPDLC). Interleukin (IL)-4 induced CCL11 production, but TGF-β1 did not, in HPDLC. However, TGF-β1 enhanced CCL11 production in IL-4-stimulated HPDLC. Western blot analysis showed that the signal transducer and activator of transcription 6 (STAT6) pathway was highly activated in HPDLC that had been stimulated with both IL-4 and TGF-β1. Mitogen-activated protein kinase activation did not differ between the HPDLC treated with a combination of IL-4 and TGF-β1 and those treated with IL-4 or TGF-β1 alone. Moreover, a STAT6 inhibitor significantly inhibited CCL11 production in HPDLC that had been stimulated with IL-4 and TGF-β1. The current study clearly demonstrated that TGF-β1 enhanced IL-4-induced CCL11 production in HPDLC. The STAT6 pathway is important for CCL11 production in IL-4- and TGF-β1-treated HPDLC

Nobiletin Inhibits Inflammatory Reaction in Interleukin-1β-Stimulated Human Periodontal Ligament Cells

The immune response in periodontal lesions is involved in the progression of periodontal disease. Therefore, it is important to find a bioactive substance that has anti-inflammatory effects in periodontal lesions. This study aimed to examine if nobiletin, which is found in the peel of citrus fruits, could inhibit inflammatory responses in interleukin (IL)-1β-stimulated human periodontal ligament cells (HPDLCs). The release of cytokines (IL-6, IL-8, CXCL10, CCL20, and CCL2) and matrix metalloproteinases (MMP-1 and MMP-3) was assessed by ELISA. The expression of cell adhesion molecules (ICAM-1and VCAM-1) and the activation of signal transduction pathways (nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt)) in HPDLCs were detected by Western blot analysis. Our experiments revealed that nobiletin decreased the expression of inflammatory cytokines, cell adhesion molecules, and MMPs in IL-1β-stimulated HPDLCs. Moreover, we revealed that nobiletin treatment could suppress the activation of the NF-κB, MAPKs, and Akt pathways. These findings indicate that nobiletin could inhibit inflammatory reactions in IL-1β-stimulated HPDLCs by inhibiting multiple signal transduction pathways, including NF-κB, MAPKs, and Akt

The Polymethoxy Flavonoid Sudachitin Inhibits Interleukin-1β-Induced Inflammatory Mediator Production in Human Periodontal Ligament Cells

Sudachitin, which is a polymethoxylated flavonoid found in the peel of Citrus sudachi, has some biological activities. However, the effect of sudachitin on periodontal resident cells is still uncertain. The aim of this study was to examine if sudachitin could decrease the expression of inflammatory mediators such as cytokines, chemokines, or matrix metalloproteinase (MMP) in interleukin- (IL-) 1β-stimulated human periodontal ligament cells (HPDLC). Sudachitin inhibited IL-1β-induced IL-6, IL-8, CXC chemokine ligand (CXCL)10, CC chemokine ligand (CCL)2, MMP-1, and MMP-3 production in HPDLC. On the other hand, tissue inhibitor of metalloproteinase- (TIMP-) 1 expression was increased by sudachitin treatment. Moreover, we found that the nuclear factor- (NF-) κB and protein kinase B (Akt) pathways in the IL-1β-stimulated HPDLC were inhibited by sudachitin treatment. These findings indicate that sudachitin is able to reduce inflammatory mediator production in IL-1β-stimulated HPDLC by inhibiting NF-κB and Akt pathways

6-(Methylsulfinyl) Hexyl Isothiocyanate Inhibits IL-6 and CXCL10 Production in TNF-α-Stimulated Human Oral Epithelial Cells

6-(Methylsulfinyl) hexyl isothiocyanate (6-MSITC) is a bioactive substance found in wasabi (Wasabia japonica) and has been reported to have some bioactive effects including anticancer and antioxidant effects. However, there are no reports on its effects on periodontal resident cells, and many points remain unclear. In this study, we aimed to investigate whether 6-MSITC exerts anti-inflammatory effects on human oral epithelial cells, including effects on signal transduction pathway activation. 6-MSITC inhibited interleukin (IL)-6 and C-X-C motif chemokine ligand 10 (CXCL10) production in TNF-α-stimulated TR146 cells, which are a human oral epithelial cell line. Moreover, we found that 6-MSITC could suppress signal transducer and activator of transcription (STAT)3, nuclear factor (NF)-κB, and p70S6 kinase (p70S6K)-S6 ribosomal protein (S6) pathways activation in TNF-α-stimulated TR146 cells. Furthermore, STAT3 and NF-κB inhibitors could suppress IL-6 and CXCL10 production in TNF-α-treated TR146 cells. In summary, 6-MSITC could decrease IL-6 and CXCL10 production in human oral epithelial cell by inhibiting STAT3 and NF-κB activation

IL-27 Modulates Chemokine Production in Oral Epithelial Cells

Background/Aims: Interleukin-27 (IL-27) is a cytokine which belongs to the IL-12 family. However, the role of IL-27 in the pathogenesis of periodontal disease is uncertain. The aim of this study was to examine the effect of IL-27 on chemokine production in TNF-α-stimulated human oral epithelial cells (TR146). Methods: We measured chemokine production in TR146 by ELISA. We used western blot analysis to detect the phosphorylation levels of signal transduction molecules, including STAT1 and STAT3 in TR146. We used inhibitors to examine the role of STAT1 and STAT3 activation. Results: IL-27 increased CXCR3 ligands production in TNF-α-stimulated TR146. Meanwhile, IL-27 suppressed IL-8 and CCL20 production induced by TNF-α. STAT1 phosphorylation level in IL-27 and TNF-α-stimulated TR146 was enhanced in comparison to TNF-α-stimulated TR146. STAT3 phosphorylation level in IL-27-treated TR146 did not change by TNF-α. Both STAT1 inhibitor and STAT3 inhibitor decreased CXCR3 ligands production. STAT1 inhibitor overrode the inhibitory effect of IL-27 on IL-8 and CCL20 production in TNF-α-stimulated TR146. Meanwhile, STAT3 inhibitor did not modulate IL-8 and CCL20 production. Conclusion: IL-27 might control leukocyte migration in periodontal lesion by modulating chemokine production from epithelial cells

The Anti-Inflammatory Effects of Iberin on TNF-α-Stimulated Human Oral Epithelial Cells : In Vitro Research

Iberin is a bioactive chemical found in cruciferous plants that has been demonstrated to have anticancer properties. However, there have been no reports on its effects on periodontal resident cells, and many questions remain unanswered. The aim of this study was to examine whether iberin had anti-inflammatory effects on human oral epithelial cells, including influences on signal transduction pathway activation in TNF-α-στιμυλατεd χελλσ. Iberin inhibited the production of interleukin (IL)-6 and C-X-C motif chemokine ligand 10 (CXCL10), as well as the expression of vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 in tumor necrosis factor (TNF)-α-stimulated TR146 cells, a human oral epithelial cell line. Moreover, iberin administration increased the expression of antioxidant signaling pathways, such as Heme Oxygenase (HO)-1 and NAD(P)H quinone dehydrogenase 1 (NQO1). Furthermore, we found that iberin could inhibit the activation of the nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT)3, and p70S6 kinase (p70S6K)-S6 ribosomal protein (S6) pathways in TNF-α-stimulated TR146 cells. In conclusion, iberin reduced inflammatory mediator expression in human oral epithelial cells by preventing the activation of particular signal transduction pathways

IL-29 enhances CXCL10 production

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 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

genipinはTNF-αが誘導するヒト歯根膜細胞のMMP-1およびMMP-3産生を抑制する

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)-a-stimulated human periodontal ligament cells (HPDLCs). Genipin prevented TNF-a- 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-a-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-a-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

Melatonin inhibits CXCL10 and MMP-1 production

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 IκB-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