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Development and Functional Characterization of Murine Tolerogenic Dendritic Cells
Published on: May 18, 2018
Dexamethasone impairs the differentiation and maturation of murine dendritic cells by Toll-like receptor 4-nuclear
Xiao-kui He1, Xiang-ling Wu, Xiu-juan He
1Department of Immunology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China.
Background:
Recent studies have demonstrated that dexamethasone (DEX) interferes with immune responses by targeting key functions of dendritic cells (DCs) at the earliest stage. However, the cellular and molecular mechanisms are still incompletely understood. This study aimed to explore the possible mechanisms by investigating the roles of DEX on differentiation, maturation & function of murine DCs and the effects of DEX on DCs via Toll-like receptor 4 (TLR4)-nuclear factor (NF)-kappaB mediated signal pathway.
Methods:
Immature DCs (imDCs) were cultured from murine bone marrow (BM) cells. We added DEX into culture medium at different time. The expression of CD11c, CD86 and I-A(b) (mouse MHC class II molecule) was determined by flow cytometry. We determined the expression of NF-kappaB and its inhibitory protein I-kappaBalpha by electrophoretic mobility shift assay (EMSA) and Western blotting, respectively. The productions of interleukin (IL)-12p70 and IL-10 in cell culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA).
Results:
DEX impaired differentiation of DCs from murine bone marrow progenitors, and inhibited lipopolysaccharide (LPS) induced maturation of DCs. DEX significantly inhibited NF-kappaB expression of normal DCs, the higher the DEX concentration or the longer the DEX treatment time, the more obvious the effect. However, DEX had little effect on LPS-induced NF-kappaB activation, and partially impaired LPS-induced I-kappaBalpha degradation. DEX significantly decreased LPS induced IL-12p70 production by DCs. Interestingly, our results showed a synergistic effect between DEX and LPS on the production of IL-10 by DCs.
Conclusions:
DEX inhibits the differentiation and maturation of murine DCs involved in TLR4-I-kappaB-NF-kappaB pathway, and also indirectly impairs Th1 development and interferes with the Th1-Th2 balance through IL-12 and/or IL-10 secretion by DCs.
Insights
Dexamethasone (DEX) impairs dendritic cell (DC) differentiation and maturation by affecting the Toll-like receptor 4 (TLR4)-nuclear factor (NF)-kappaB pathway. This impacts immune responses by altering cytokine production, specifically IL-12 and IL-10.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Dexamethasone (DEX) is known to interfere with immune responses by targeting dendritic cells (DCs).
- The precise cellular and molecular mechanisms underlying DEX's effects on DCs remain incompletely understood.
- This study investigates DEX's impact on murine DC differentiation, maturation, and function, focusing on the Toll-like receptor 4 (TLR4)-nuclear factor (NF)-kappaB signaling pathway.
Purpose of the Study:
- To elucidate the mechanisms by which DEX affects murine dendritic cell differentiation, maturation, and function.
- To investigate the role of the TLR4-NF-kappaB signaling pathway in mediating DEX's effects on DCs.
- To analyze the impact of DEX on DC cytokine production (IL-12p70 and IL-10).
Main Methods:
- Murine bone marrow-derived immature dendritic cells (imDCs) were cultured.
- DEX was added to cultures at varying concentrations and durations.
- Flow cytometry, electrophoretic mobility shift assay (EMSA), Western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to assess DC markers, NF-kappaB activation, I-kappaBalpha degradation, and cytokine production.
Main Results:
- DEX impaired the differentiation of DCs from bone marrow progenitors and inhibited lipopolysaccharide (LPS)-induced DC maturation.
- DEX significantly inhibited NF-kappaB expression in normal DCs, with effects increasing with DEX concentration and treatment time.
- DEX had minimal impact on LPS-induced NF-kappaB activation but partially impaired LPS-induced I-kappaBalpha degradation, decreased IL-12p70 production, and showed a synergistic effect with LPS on IL-10 production.
Conclusions:
- DEX inhibits murine DC differentiation and maturation via the TLR4-I-kappaB-NF-kappaB pathway.
- DEX indirectly impairs T helper 1 (Th1) development.
- DEX interferes with the Th1-Th2 balance through modulation of IL-12 and IL-10 secretion by DCs.
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