Expression of programmed death 1 ligand 1 on periodontal tissue cells as a possible protective feedback mechanism against periodontal tissue destruction

Zhang, Jiehua; Wang, Chieh‐Mei; Zhang, Ping; Wang, Xiaoqian; Chen, Jiao; Yang, Jun; Lu, Wanlu; Zhou, Wenjie; Yuan, Wenwen; Feng, Yun

doi:10.3892/mmr.2016.4824

Cited by 33 publications

(48 citation statements)

References 33 publications

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“…The extracted teeth were rinsed and placed in phosphate-buffered saline (PBS) supplemented with 1,000 IU/ml penicillin and 1,000 μg/ml streptomycin (HyClone). The remaining procedures were performed according to a previously described protocol (20). Periodontal tissues were from the middle third of the root, were cut into 1-2 mm 2 sections and placed in culture flasks for cell culture in RPMI-1640 medium (Gibco; Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (FBS; Sigma-Aldrich; Merck KGaA), 100 IU/ml penicillin and 100 μg/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase D3 regulates the expression of the immunosuppressive protein, PD‑L1, through STAT1/STAT3 signaling

et al. 2020

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Oral squamous cell carcinoma (OSCC) is capable of constructing a favorable immune escape environment through interactions of cells with cells and of cells with the environment. Programmed death ligand-1 (PD-L1) is a well-recognized inhibitor of anti-tumor immunity that plays an important role in tumor immune escape. However, the molecular mechanisms regulating PD-L1 expression are not yet fully understood. In this study, to investigate the role of protein kinase D3 (PKD3) in the regulation of PD-L1 expression, the expression and correlation of PKD3 and PD-L1 were first analyzed by the immunostaining of human OSCC tissue sections, cell experiments and TCGA gene expression databases. The expression levels of PKD3 and PD-L1 were found to be significantly higher in OSCC cells than in normal tissues or cells. In addition, the expression levels of PKD3 and PD-L1 were found to be significantly positively correlated. Subsequently, it was found that the levsel of PD-L1 expression decreased following the silencing of PKD3 and that the ability of interferon (IFN)-γ to induce PD-L1 expression was also decreased in OSCC. The opposite phenomenon occurred following the overexpression of PKD3. It was also found that the phosphorylation of signal transducer and activator of transcription (STAT)1/STAT3 was reduced by the knockdown of PKD3 in OSCC. Moreover, the expression level of PD-L1 was decreased after the use of siRNA to knockdown STAT1 or STAT3. On the whole, the findings of this study confirm that PKD3 regulates the expression of PD-L1 induced by IFN-γ by regulating the phosphorylation of STAT1/STAT3. These findings broaden the understanding of the biological function of PKD3, suggesting that PKD is a potential therapeutic target for OSCC.

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Section: Methodsmentioning

confidence: 99%

Protein kinase D3 regulates the expression of the immunosuppressive protein, PD‑L1, through STAT1/STAT3 signaling

et al. 2020

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“…2.4.1. hPDLSCs Treatment 24 h after seeding an appropriate number of hPDLSCs in 6-well plates, these cells were stimulated with either 5 ng/ml IL-1β [18] or 10 ng/ml TNF-α [20] or 100 ng/ml IFN-γ [21] (all from Invivogen, San Diego, USA) in FBS-free DMEM for all performed experiments. After 48 h incubation, hPDLSCs were proceeded as indicated below.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Cytokines Differently Define the Immunomodulation of Mesenchymal Stem Cells from the Periodontal Ligament

Behm

Blufstein

Gahn

et al. 2020

Cells

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Human periodontal ligament stem cells (hPDLSCs) play an important role in periodontal tissue homeostasis and regeneration. The function of these cells in vivo depends largely on their immunomodulatory ability, which is reciprocally regulated by immune cells via cytokines, particularly interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Different cytokines activate distinct signaling pathways and might differently affect immunomodulatory activities of hPDLSCs. This study directly compared the effect of IFN-γ, TNF-α, or IL-1β treated primary hPDLSCs on allogenic CD4+ T lymphocyte proliferation and apoptosis in an indirect co-culture model. The effects of IFN-γ, TNF-α, and IL-1β on the expression of specific immunomodulatory factors such as intoleamine-2,3-dioxygenase-1 (IDO-1), prostaglandin E2 (PGE2), and programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) in hPDLSCs were compared. The contribution of different immunomodulatory mediators to the immunomodulatory effects of hPDLSCs in the indirect co-culture experiments was assessed using specific inhibitors. Proliferation of CD4+ T lymphocytes was inhibited by hPDLSCs, and this effect was strongly enhanced by IFN-γ and IL-1β but not by TNF-α. Apoptosis of CD4+ T lymphocytes was decreased by hPDLSCs per se. This effect was counteracted by IFN-γ or IL-1β. Additionally, IFN-γ, TNF-α, and IL-1β differently regulated all investigated immunomediators in hPDLSCs. Pharmacological inhibition of immunomediators showed that their contribution in regulating CD4+ T lymphocytes depends on the cytokine milieu. Our data indicate that inflammatory cytokines activate specific immunomodulatory mechanisms in hPDLSCs and the expression of particular immunomodulatory factors, which underlies a complex reciprocal interaction between hPDLSCs and CD4+ T lymphocytes.

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“…PD-L1 is an important immune checkpoint molecule in cancer pathogenesis regulating both tumor-intrinsic signaling and adaptive immunosuppression. It is induced by inflammatory and gamma-chain cytokines [15][16][17]20]. However, little is known about other factors in the oral cavity that also influence PD-L1 expression in SCC.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction of PD-L1 with PD-1 regulates the balance between co-stimulatory and co-inhibitory immune signals, maintains the breadth and magnitude of the immune response, maintains self-tolerance, prevents adverse autoimmune inflammatory events, protects the host from uncontrolled immune responses to pathogens, and prevents inflammatory tissue damage. Increases in PD-L1 expression can occur on SCC cells [8] as a result of mutations in tumor cell signaling pathways or exposure of tumor cells to inflammatory cytokines IL-1, IL-6, GM-CSF, IFNγ, TNFα, and VEGF [15][16][17][18][19] and the gamma-chain cytokines IL-2, IL-7, IL-10, IL-15, and IL-21 [20]. The latter group plays a role in peripheral T-cell expansion and survival.…”

Section: Introductionmentioning

confidence: 99%

HBD3 Induces PD-L1 Expression on Head and Neck Squamous Cell Carcinoma Cell Lines

et al. 2019

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Human β-defensin 3 (HBD3) is an antimicrobial peptide up-regulated in the oral tissues of individuals with head and neck squamous cell carcinomas (HNSCC) and oral squamous cell carcinomas (SCC) and present in high concentrations in their saliva. In this study, we determined if HBD3 contributes to HNSCC pathogenesis by inducing programmed death-ligand 1 (PD-L1) expression on HNSCC cell lines. For this, SCC cell lines SCC4, SCC15, SCC19, SCC25, and SCC99 (5.0 × 104 viable cells) were used. Cells were incubated with IFNγ (0.6 µM) and HBD3 (0.2, 2.0, or 20.0 µM) for 24 h. Cells alone served as controls. Cells were then treated with anti-human APC-CD274 (PD-L1) and Live/Dead Fixable Green Dead Cell Stain. Cells treated with an isotype antibody and cells alone served as controls. All cell suspensions were analyzed in a LSR II Violet Flow Cytometer. Cytometric data was analyzed using FlowJo software. Treatment with IFNγ (0.6 µM) increased the number of cells expressing PD-L1 (p < 0.05) with respect to controls. Treatment with HBD3 (20.0 µM) also increased the number of cells expressing PD-L1 (p < 0.05) with respect to controls. However, treatment with IFNγ (0.6 µM) was not significantly different from treatment with HBD3 (20.0 µM) and the numbers of cells expressing PD-L1 were similar (p = 1). Thus, HBD3 increases the number of cells expressing PD-L1. This is a novel concept, but the role HBD3 contributes to HNSCC pathogenesis by inducing PD-L1 expression in tumors will have to be determined.

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Expression of programmed death 1 ligand 1 on periodontal tissue cells as a possible protective feedback mechanism against periodontal tissue destruction

Cited by 33 publications

References 33 publications

Protein kinase D3 regulates the expression of the immunosuppressive protein, PD‑L1, through STAT1/STAT3 signaling

Protein kinase D3 regulates the expression of the immunosuppressive protein, PD‑L1, through STAT1/STAT3 signaling

Cytokines Differently Define the Immunomodulation of Mesenchymal Stem Cells from the Periodontal Ligament

HBD3 Induces PD-L1 Expression on Head and Neck Squamous Cell Carcinoma Cell Lines

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