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Stimulation of tolerogenic dendritic cells using dexamethasone and 1,25-dihydroxyvitamin D3 represses autologous T cell activation and chondrocyte inflammation.

ABSTRACT: Human osteoarthritis (OA) has been reclassified as a systemic musculoskeletal disorder involving activation of the innate and adaptive immune systems. Elevated pro-inflammatory cytokines may serve a key function in the development of the disease. 1,25-Dihydroxyvitamin D3 and dexamethasone (vitD3/Dex) may inhibit inflammation by acting on tolerogenic dendritic cells (tolDCs) in chronic inflammatory conditions. In the present study, DCs were isolated from peripheral blood mononuclear cells of patients with OA. DCs expressing high levels of co-stimulatory molecules maintain a tolerogenic phenotype under stimulation with LPS, which promotes DC maturation to generate tolDCs. When vitD3/Dex were added in the current study, the tolDCs produced pro-inflammatory cytokines, including low levels of tumor necrosis factor-?, interleukin (IL)-1?, IL-6 and IL-10, and high levels of transforming growth factor-?. However, when vitD3/Dex were added to DCs without LPS stimulation, the levels of IL-10 were high. DCs with LPS stimulation increased the percentage of T-cells that produced IFN-? and IL-17 and DCs with vitD3/Dex treatment alone increased the percentage of T-cells that produced IL-10 and FoxP3. However, those cytokines decrease in DCs co-processed with LPS and vitD3/Dex. The IL-10 release by the stimulated T cells was indicated to repress autologous T cell proliferation via soluble IL-10 and cell-cell contact. Furthermore, tolDCs and regulatory T cells suppressed matrix metalloproteinase (MMP)-1 and MMP-13 secretion by chondrocytes. Additionally, Akt and p38 mitogen-activated protein kinase signaling were demonstrated to be involved in the regulatory effects of Dec and vitD3 in DCs. The present findings suggest a novel mechanism underlying the beneficial effects of tolDCs, particularly in association with the pathogenesis of OA.

SUBMITTER: Wang G

PROVIDER: S-EPMC6307353 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Stimulation of tolerogenic dendritic cells using dexamethasone and 1,25-dihydroxyvitamin D3 represses autologous T cell activation and chondrocyte inflammation.

Wang Gaoyuan G Zhang Junqiang J Fang Yuan Y Cao Wei W Xu Bin B Chen Xiaoyu X

Experimental and therapeutic medicine 20181130 1

Human osteoarthritis (OA) has been reclassified as a systemic musculoskeletal disorder involving activation of the innate and adaptive immune systems. Elevated pro-inflammatory cytokines may serve a key function in the development of the disease. 1,25-Dihydroxyvitamin D3 and dexamethasone (vitD3/Dex) may inhibit inflammation by acting on tolerogenic dendritic cells (tolDCs) in chronic inflammatory conditions. In the present study, DCs were isolated from peripheral blood mononuclear cells of pati ...[more]

PMID: 30651850

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Project description:The effect of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] on 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism was examined in rats fed on a low-calcium diet. These rats exhibit hypocalcaemia, high urinary cyclic AMP excretion, a markedly elevated serum 1,25(OH)2D concentration and low serum concentrations of both 24,25(OH)2D and 25(OH)D. When the rats are treated orally with 1, 5 or 10 micrograms of 24,25(OH)2D3/100 g every day, there is a dramatic decrease in serum 1,25(OH)2D concentration in a dose-dependent manner concomitant with an increase in serum 24,25(OH)2D concentration. Serum calcium concentration and urinary cyclic AMP excretion are not significantly affected by the 24,25(OH)2D3 treatment, which suggests that parathyroid function is not affected by the 24,25(OH)2D3 treatment. The 25(OH)D3 1 alpha-hydroxylase activity measured in kidney homogenates is markedly elevated in rats on a low-calcium diet but is not affected by any doses of 24,25(OH)2D3. In contrast, recovery of intravenously injected [3H]1,25(OH)2D3 in the serum is decreased in 24,25(OH)2D3-treated rats. Furthermore, when [3H]1,25(OH)2D3 is incubated in vitro with kidney or intestinal homogenates of 24,25(OH)2D3-treated rats there is a decrease in the recovery of radioactivity in the total lipid extract as well as in the 1,25(OH)2D3 fraction along with an increase in the recovery of radioactivity in the water-soluble phase. These results are consistent with the possibility that 24,25(OH)2D3 has an effect on 1,25(OH)2D3 metabolism, namely that of enhancing the degradation of 1,25(OH)2D3. However, because a considerable proportion of the injected 24,25(OH)2D3 is expected to be converted into 1,24,25(OH)3D3 by renal 1 alpha-hydroxylase in 24,25(OH)2D3-treated rats, at least a part of the decrease in serum 1,25(OH)2D concentration may be due to a competitive inhibition by 24,25(OH)2D3 of the synthesis of 1,25(OH)2D3 from 25(OH)D3. Thus the physiological importance of the role of 24,25(OH)2D3 in regulating the serum 1,25(OH)2D concentration as well as the mechanism and metabolic pathway of degradation of 1,25(OH)2D3 remain to be clarified.

Dataset Information

Stimulation of tolerogenic dendritic cells using dexamethasone and 1,25-dihydroxyvitamin D3 represses autologous T cell activation and chondrocyte inflammation.

Publications

Stimulation of tolerogenic dendritic cells using dexamethasone and 1,25-dihydroxyvitamin D3 represses autologous T cell activation and chondrocyte inflammation.

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