(-)-Epigallocatechin-3-Gallate Inhibits CC Chemokine Ligand 11 Production in Human Gingival Fibroblasts

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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.

Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

IL-4 Modulates CCL11 and CCL20 Productions from IL-1β-Stimulated Human Periodontal Ligament Cells

Hosokawa

Hosokawa²,

Shindo

et al. 2016

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“…We previously reported that TNF-α-stimulated periodontium constitution cells could produce chemokines which have already participated in neutrophils [6], Th1 cells [7], Th2 cells [8], and Th17 cells infiltration [9]. However, we do not understand the mechanism how chemokine production is controlled in periodontal lesion enough because new inflammatory mediator expressions are reported.…”

Section: Introductionmentioning

confidence: 99%

IL-27 Modulates Chemokine Production in TNF-α -Stimulated Human Oral Epithelial Cells

Hosokawa

Ozaki

et al. 2017

Self Cite

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.

“…Further, elevated levels of activated p38α MAPK in inflamed tissue of patients with rheumatoid arthritis (RA) [3], Crohn's disease (CD) [4] and chronic obstructive pulmonary disease (COPD) [5] confirmed these key signalling molecules as therapeutic targets. Moreover, various disorders were connected with p38 MAPK signalling pathway such as artheriosclerosis [6,7] (via increased production of proinflammatory cytokines induced by oxidized low-density lipoprotein in human mast cell line and by inhibition of the formation of human macrophage-derived foam cells), platelet activation and thrombus formation [8] (through abrogation of p38 MAPKdependent phosphorylation of platelet cytosolic phospholipase A2), diabetic peripheral neuropathy [9] (by activated CD8(+)-T-cells mediating cytotoxicity toward Schwann cells), periodontal disease [10] (via modulation of CC chemokine ligand 11 (CCL11) related Th2 cells migration in human gingival fibroblasts), inflammation in human pulmonary epithelial cells [11] (through TNF-α triggered chemokine CXCL1 release) and induced proinflammatory cytokines production in macrophages [12] (via IL-17A). However, up to now, several generations of p38 MAP kinase inhibitors failed in clinical trials predominantly due to lack of efficacy and/or a poor safety profile [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC₅₀ values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.