Secretory leukocyte protease inhibitor regulates human periodontal ligament cell production of pro-inflammatory cytokines

Svensson, Daniel; Aidoukovitch, Alexandra; Anders, Emma; Jönsson, Daniel; Nebel, Daniel; Nilsson, Bengt‐Olof

doi:10.1007/s00011-017-1062-2

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Protein levels of CXCL1 (d), CCL2 (e), and CCL5 (f) in supernatants of human periodontal fibroblasts exposed to F. nucleatum and/or constant tensile strain (CTS) at 1 day and 2 days, as analyzed by ELISA. Mean values and SEM (n = 9/group), *significant (p < 0.05) difference between groups CCL2, and CCL5 expressions in human periodontal cells [38][39][40][41][42]. By demonstrating that these chemokines are upregulated in response to microbial stimuli, these studies support our in vitro findings.…”

Section: Discussionsupporting

confidence: 84%

CXCL1, CCL2, and CCL5 modulation by microbial and biomechanical signals in periodontal cells and tissues—in vitro and in vivo studies

et al. 2020

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Objectives This study was established to investigate whether the chemokines CXCL1, CCL2, and CCL5 are produced in periodontal cells and tissues and, if so, whether their levels are regulated by microbial and/or mechanical signals. Materials and methods The chemokine expression and protein levels in gingival biopsies from patients with and without periodontitis were analyzed by RT-PCR and immunohistochemistry. The chemokines were also analyzed in gingival biopsies from rats subjected to experimental periodontitis and/or orthodontic tooth movement. Additionally, chemokine levels were determined in periodontal fibroblasts exposed to the periodontopathogen Fusobacterium nucleatum and mechanical forces by RT-PCR and ELISA. Results Higher CXCL1, CCL2, and CCL5 levels were found in human and rat gingiva from sites of periodontitis as compared with periodontally healthy sites. In the rat experimental periodontitis model, the bacteria-induced upregulation of these chemokines was significantly counteracted by orthodontic forces. In vitro, F. nucleatum caused a significant upregulation of all chemokines at 1 day. When the cells were subjected simultaneously to F. nucleatum and mechanical forces, the upregulation of chemokines was significantly inhibited. The transcriptional findings were paralleled at protein level. Conclusions This study provides original evidence in vitro and in vivo that the chemokines CXCL1, CCL2, and CCL5 are regulated by both microbial and mechanical signals in periodontal cells and tissues. Furthermore, our study revealed that biomechanical forces can counteract the stimulatory actions of F. nucleatum on these chemokines. Clinical relevance Mechanical loading might aggravate periodontal infection by compromising the recruitment of immunoinflammatory cells.

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Section: Discussionsupporting

confidence: 84%

CXCL1, CCL2, and CCL5 modulation by microbial and biomechanical signals in periodontal cells and tissues—in vitro and in vivo studies

et al. 2020

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“…We have shown by immunocytochemistry and Western blot that PDL cells express SLPI, although PDL cells show much lower expression of the protein compared to HaCaT cells 17 . E coli LPS increases both IL‐6 and MCP‐1 mRNA in PDL cells, whereas it has no effect in HaCaT cells, and thus, expression levels of SLPI negatively correlate with pro‐inflammatory cytokine expression 17 . Knockdown of PDL cell SLPI gene activity by siRNA enhances both basal and LPS‐stimulated IL‐6 and MCP‐1 expression, providing further evidence that SLPI indeed is a negative regulator of PDL cell production of pro‐inflammatory cytokines 17 .…”

Section: Human Pdl Cells Express Slpi and Cellular Levels Of Slpi Negmentioning

confidence: 83%

“…Intracellular SLPI has been shown to translocate from cytoplasm to nucleus and interact with NF‐κB signaling in monocytes 68 . We have shown by immunocytochemistry and Western blot that PDL cells express SLPI, although PDL cells show much lower expression of the protein compared to HaCaT cells 17 . E coli LPS increases both IL‐6 and MCP‐1 mRNA in PDL cells, whereas it has no effect in HaCaT cells, and thus, expression levels of SLPI negatively correlate with pro‐inflammatory cytokine expression 17 .…”

Section: Human Pdl Cells Express Slpi and Cellular Levels Of Slpi Negmentioning

confidence: 90%

“…Hence, LL‐37 seems to act anti‐inflammatory through an intracellular mechanism of action in PDL cells. Moreover, the protein secretory leukocyte protease inhibitor (SLPI), endogenously expressed by PDL cells, has recently been shown to act as a negative regulator of PDL cell pro‐inflammatory cytokine production, indicating that proteins expressed by PDL cells themselves also can modulate their production of cytokines 17 …”

Section: Introductionmentioning

confidence: 99%

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Mechanisms involved in regulation of periodontal ligament cell production of pro‐inflammatory cytokines: Implications in periodontitis

Nilsson

2020

J of Periodontal Research

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It is well recognized that human periodontal ligament cells (PDL cells) may represent local immune cells of the periodontal tissues. However, it is unclear whether they represent “true” immune cells, since they can produce pro‐inflammatory cytokines not only after stimulation with bacterial lipopolysaccharides but also in response to other stimuli such as mechanical stress. Stimulation with bacterial lipopolysaccharides strongly enhances PDL cell production of pro‐inflammatory cytokines through activation of toll‐like receptors and NF‐κB signaling. Less information is available regarding putative modulators of cytokine production and their mechanisms of action in PDL cells. The anti‐inflammatory glucocorticoid dexamethasone reduces lipopolysaccharide‐induced PDL cell production of cytokines. Recent observations show that vitamin D and the antimicrobial peptide LL‐37 antagonize lipopolysaccharide‐stimulated PDL cell production of pro‐inflammatory cytokines. Secretory leukocyte protease inhibitor is endogenously expressed by PDL cells, and this protein negatively regulates PDL cell‐evoked cytokine production. More information and knowledge about the regulation of PDL cell production of cytokines may clarify the role of PDL cells in oral innate immunity and their importance in periodontitis.

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“…Although high levels of MMP-9 proteins were observed with or without LPS treatment, Slpi −/− BMEos showed augmented invasive activity upon stimulation, suggesting that MMP-9 augmentation is barely involved in the LPS-induced invasion of Slpi −/− BMEos. A recent study demonstrated that the knockdown of SLPI by siRNA upregulated the expression of monocyte chemotactic protein-1 in LPS-treated periodontal ligament cells ( 58 ). Our microarray data also showed that several genes of chemokines and chemokine receptors are expressed in both B6 and Slpi −/− BMEos (GSE87638).…”

Section: Discussionmentioning

confidence: 99%

Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells

et al. 2017

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Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is expressed in basophils and eosinophils but in not in mast cells. SLPI-deficient (Slpi−/−) basophils produce more cytokines than wild-type mice after IgE stimulation. Although the deletion of SLPI in basophils did not affect the release of chemical mediators upon IgE stimulation, the enzymatic activity of the serine protease tryptase was increased in Slpi−/− basophils. Mice transferred with Slpi−/− basophils were highly sensitive to IgE-mediated chronic allergic inflammation. Eosinophils lacking SLPI showed greater interleukin-6 secretion and invasive activity upon lipopolysaccharide stimulation, and the expression of matrix metalloproteinase-9 by these eosinophils was increased without stimulation. The absence of SLPI increases JNK1 phosphorylation at the steady state, and augments the serine phosphorylation of JNK1-downstream ETS transcriptional factor Elk-1 in eosinophils upon stimulation. Of note, SLPI interacts with a scaffold protein, JNK-interacting protein 3 (JIP3), that constitutively binds to the cytoplasmic domain of toll-like receptor (TLR) 4, suggesting that SLPI controls Elk-1 activation via binding to JIP3 in eosinophils. Mice transferred with Slpi−/− eosinophils showed the exacerbation of chitin-induced allergic inflammation. These findings showed that SLPI is a negative regulator in allergic effector cells and suggested a novel inhibitory role of SLPI in the TLR4 signaling pathways.

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Secretory leukocyte protease inhibitor regulates human periodontal ligament cell production of pro-inflammatory cytokines

Cited by 19 publications

References 32 publications

CXCL1, CCL2, and CCL5 modulation by microbial and biomechanical signals in periodontal cells and tissues—in vitro and in vivo studies

CXCL1, CCL2, and CCL5 modulation by microbial and biomechanical signals in periodontal cells and tissues—in vitro and in vivo studies

Mechanisms involved in regulation of periodontal ligament cell production of pro‐inflammatory cytokines: Implications in periodontitis

Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells

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