Dexamethasone Induces IL‐10‐Producing Monocyte‐Derived Dendritic Cells with Durable Immaturity

Abstract

It is highly desirable that immature dendritic cells (DC) used for tolerance induction maintain steady immature state with predominant interleukin (IL)-10 production. In this study, we attempted to develop DC with durable immaturity and other tolerogenic features by using dexamethasone (Dex). We found DC derived from human monocytes in the presence of 10 À7 M Dex were negative for CD1a. Compared with control transduced DC (Ctrl-DC), Dex-DC expressed lower CD40, CD80 and CD86 but equivalent human leucocyte antigen-DR. Both immature Dex-and Ctrl-DC did not express CD83. Nevertheless, upon stimulation of lipopolysaccharide (LPS) or CD40 ligand, the expression of CD40, CD80, CD83 and CD86 was upregulated on Ctrl-DC but not on Dex-DC. The immaturity of Dex-DC was durable following Dex removal. Interestingly, Dex-DC maintained production of large amount of IL-10 and little IL-12 five days after Dex removed. Further study indicated that high-level IL-10 production by Dex-DC was associated with high-level phosphorylation of extracellular signal-regulated kinase (ERK) as blockade of this enzyme markedly attenuated IL-10 production. Furthermore, Dex-DC sustained the capability of high phosphorylation of ERK and IL-10 production 5 days after Dex removal. In addition, Dex-DC had significantly lower activity in stimulating T-cell proliferation. Neutralization of IL-10, to some extent, promoted DC maturation activated by LPS, as well as T-cell stimulatory activity of Dex-DC. The above findings suggest that IL-10-producing Dex-DC with durable immaturity are potentially useful for induction of immune tolerance.

Induction of Treg by monocyte‐derived DC modulated by vitamin D3 or dexamethasone: Differential role for PD‐L1

“…Similar observations have been made with human moDC treated with Dex [10,17]. In addition, Dex-DC possess durable immaturity [10] as high IL-10 and little IL-12 production was maintained up to 5 days after removal of Dex. In vivo, application of Dex-DC prior to allograft transplantation significantly prolonged the survival of the grafts in an antigendependent fashion in mice [16,18].…”

“…For example, DC treated with either dexamethasone (Dex) or the active form of vitamin D, 1a,25-dihydroxyvitamin D 3 (VD3), arrest DC in a semimature state and prevent the up-regulation of co-stimulatory Treatment of murine immature bone marrow-derived DC with Dex prior to LPS-induced activation results in modulated DC that inhibit the proliferation of allo-specific T cells in both primary and secondary MLR [8,16]. Similar observations have been made with human moDC treated with Dex [10,17]. In addition, Dex-DC possess durable immaturity [10] as high IL-10 and little IL-12 production was maintained up to 5 days after removal of Dex.…”

“…Priming of moDC with microbial compounds or tissue-derived factors such as IFN-g, prostaglandin E2 (PGE2) or IL-23 and IL-1 results in enhanced expression of MHC class II and co-stimulatory molecules and drives the development of effector Th1, Th2 and Th17 cells [5][6][7]. It is now clear that certain immunosuppressive drugs and anti-inflammatory agents induce DC with tolerogenic properties [8][9][10][11][12][13][14][15]. For example, DC treated with either dexamethasone (Dex) or the active form of vitamin D, 1a,25-dihydroxyvitamin D 3 (VD3), arrest DC in a semimature state and prevent the up-regulation of co-stimulatory Treatment of murine immature bone marrow-derived DC with Dex prior to LPS-induced activation results in modulated DC that inhibit the proliferation of allo-specific T cells in both primary and secondary MLR [8,16].…”

Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells

“…PC12 cells, melanocytes, gastric and intestinal epithelial cells, elevation of cAMP results in ERK1/2-activation via a B-RAF -MEK1/2 pathway [12,40,51], which may also be responsible for Ctx-induced ERK activation in porcine MoDC. Functionally, ERK1/2 activation has been associated with high levels of IL-10 secretion by DC [52], which is consistent with our findings. It has been previously demonstrated that functional DC maturation involves NFκB activation [39].…”

Role of innate immunity in tolerance induction

“…В настоящее время активно исследуется влияние различных иммуносупрессивных лекарств на дифференцировку ДК и их функцию [118]. Среди наиболее часто используемых лекарств для генерации толерогенных ДК в лабораторных условиях -дексаметазон, уже упоминавшийся витамин D 3 (1a,25(ОН) 2 D 3 и его аналоги), а также рапамицин [64,65,[119][120][121][122][123][124][125]. Все эти лекарства имеют общее свойство -они индуцируют дифференцировку фенотипически зрелых ДК, которые имеют низкую стимулирующую способность Т-клеток и не становятся иммуностимуляторами в ответ на сигналы зрелости ДК.…”