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Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells.

ABSTRACT: BACKGROUND Treg cells play a central role in the suppression of immune response, and their suppressive capacity can be modulated by toll-like receptor (TLR) ligands. However, the detailed pathway of TLR ligand modulation is still unknown. The present study aimed to evaluate the effect of the high mobility group box-1 protein 1 (HMGB1) and lipopolysaccharide (LPS) on Treg cells through TLR4 signaling. MATERIAL AND METHODS Treg cells were purified from healthy human peripheral blood mononuclear cells (PBMCs) by magnetic-bead activity cell sorting (MACS), blocked by anti-TLR4 monoclonal antibody, and then incubated with different concentration of LPS or HMGB1. The level of gene expression of IL-1?, IL-10, IFN-?, and TGF-? were detected using quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), and the proliferation of Treg cells after treating by LPS and HMGB1 was analyzed by flow cytometry. The NF-?B expression in Treg cells was examined by Western blotting. RESULTS LPS treated CD4 CD25 Treg cells directly increased the expression of IL-1b and IL-10 and decreased the expression of IFN-? and TGF-?. However, HMGB1 treatment resulted in a marked decreased expression of IL-1?, IL-10, IFN-?, and TGF-?. The proliferation of CD4+ T cells was significantly inhibited by Treg cells in the LPS treatment group, but weaken in the HMGB1 treatment group. These data suggest that HMGB1 and LPS stimulation could downregulate the expression NF-?B p65 in cytoplasmic proteins and increase the expression in nuclear proteins, thus leading to modulation of IL-1?, IL-10, IFN-?, and TGF-? expression; moreover, the suppressive function of Treg cells could be regulated by TLR4. CONCLUSIONS TLR4 signaling in HMGB1 mediated the suppressive function of Treg cells through the activation of the NF-?B pathway.

SUBMITTER: Luo C

PROVIDER: S-EPMC5267620 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells.

Luo Chunyan C Liu Huiting H Wang Hu H Wang Jiajun J

Medical science monitor : international medical journal of experimental and clinical research 20170118

BACKGROUND Treg cells play a central role in the suppression of immune response, and their suppressive capacity can be modulated by toll-like receptor (TLR) ligands. However, the detailed pathway of TLR ligand modulation is still unknown. The present study aimed to evaluate the effect of the high mobility group box-1 protein 1 (HMGB1) and lipopolysaccharide (LPS) on Treg cells through TLR4 signaling. MATERIAL AND METHODS Treg cells were purified from healthy human peripheral blood mononuclear ce ...[more]

PMID: 28096525

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Project description:Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-?B pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-?B pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner. Treatment with a TLR4 antagonist and an NF-?B inhibitor resulted in suppression of rHMGB-1-induced HESC proliferation (P<0.05). Levels of IL-6 were significantly decreased following treatment with an NF-?B inhibitor (P<0.05). Our results support the development of altered, pathological endometrium resulted from oxidative stress in normal endometrium. These findings may provide important insights into the changes in endometrium linking the development and progression of endometriosis.

Dataset Information

Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells.

Publications

Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells.

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