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The Antidiabetic Agent Metformin Inhibits IL-23 Production in Murine Bone-Marrow-Derived Dendritic Cells.

ABSTRACT: Psoriasis is a chronic inflammatory skin disease, and its immune mechanism has been profoundly elucidated. Biologics targeting interleukin (IL)-23 have prevented the development of psoriasis. As major sources of IL-23, dendritic cells (DCs) play a pivotal role in psoriasis; however, the regulatory mechanism of IL-23 in DCs remains unclear. IL-36γ was reported to reflect the disease activity of psoriasis. Therefore, we hypothesized that IL-36γ may affect IL-23 production in DCs. To reveal the mechanism by which IL-36γ controls IL-23 production in DCs, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-36γ. IL-36γ stimulation upregulated the mRNA and protein expression of Nfkbiz in BMDCs. Nfkbiz knockdown using siRNA transfection partially inhibited the upregulation of IL-23 mRNA expression induced by IL-36γ stimulation. Since NF-κB signaling regulates Nfkbiz expression and the anti-diabetic agent metformin reportedly modulates NF-κB signaling, we examined the effect of metformin treatment on IL-36γ-induced IL-23 production. Metformin treatment impaired the phosphorylation of NF-κB induced by IL-36γ stimulation with the subsequent downregulation of Nfkbiz, resulting in the inhibition of IL-23 production in BMDCs. These data provided evidence that metformin treatment can inhibit IL-36γ-mediated IL-23 production in BMDCs, which might contribute to the prevention of psoriasis.

SUBMITTER: Matsuda-Taniguchi T

PROVIDER: S-EPMC8658299 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IL-22 is rapidly induced by Pathogen Recognition Receptors Stimulation in Bone-Marrow-derived Dendritic Cells in the Absence of IL-23.

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Modulation of murine bone marrow derived dendritic cells by IL-4

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2015-04-28 | E-GEOD-59868 | biostudies-arrayexpress

Modulation of murine bone marrow derived dendritic cells by IL-4

2015-04-28 | GSE59868 | GEO

Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-? by CD4+ T cells.

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| S-EPMC1850236 | biostudies-literature

Shikonin inhibits maturation of bone marrow-derived dendritic cells and suppresses allergic airway inflammation in a murine model of asthma.

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Project description:Pro-inflammatory interleukin (IL)-17-producing ?? (??17) T cells are thought to develop exclusively in the thymus during fetal/perinatal life, as adult bone marrow precursors fail to generate ??17 T cells under homeostatic conditions. Here, we employ a model of experimental autoimmune encephalomyelitis (EAE) in which hematopoiesis is reset by bone marrow transplantation and demonstrate unequivocally that V?4+ ??17 T cells can develop de novo in draining lymph nodes in response to innate stimuli. In vitro, ?? T cells from IL-17 fate-mapping reporter mice that had never activated the Il17 locus acquire IL-17 expression upon stimulation with IL-1? and IL-23. Furthermore, IL-23R (but not IL-1R1) deficiency severely compromises the induction of ??17 T cells in EAE, demonstrating the key role of IL-23 in the process. Finally, we show, in a composite model involving transfers of both adult bone marrow and neonatal thymocytes, that induced ??17 T cells make up a substantial fraction of the total IL-17-producing V?4+ T-cell pool upon inflammation, which attests the relevance of this novel pathway of peripheral ??17 T-cell differentiation.

| S-EPMC5666615 | biostudies-literature

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells.

Project description:BACKGROUND:Ticks, as blood-feeding arthropod vectors, have evolved their own unique mechanism to suppress host immune responses and evade immune defenses in order to complete blood-feeding. The immunoregulatory effect of tick bioactive molecules on hosts has been widely reported, and the cystatin family has been identified as one of the major immunomodulators. In previous studies, we obtained a novel tick salivary bioactive protein named RHcyst-1, which belongs to the type 1 cystatin family. Here, we demonstrated the effects of RHcyst-1 on the host immune response mainly on dendritic cell (DC) function. Understanding the function of tick-derived bioactive molecule may help to clarify the mechanisms of how ticks escape the host immune response and help to control ticks and tick-borne disease transmission. METHODS:Bone marrow-derived DCs (BMDCs) were generated and induced by GM-CSF and IL-4 with or without RHcyst-1 addition. Flow cytometry was used to analyze the differentiation and maturation of BMDCs and T cell cytokine production. Quantitative real-time PCR (qRT-PCR) and western blot were used to measure changes in expression within STAT and p38 MAPK signaling pathways. RESULTS:Flow cytometry analysis revealed that RHcyst-1 inhibited the differentiation of BMDCs, but had no effect on the maturation of BMDCs. T cells co-cultured with DCs treated with RHcyst-1 produced significantly less TNF-?, IFN-? and IL-2 than the control group. Further analysis showed that the mRNA level and phosphorylation of p38, ERK and STAT were significantly changed after RHcyst-1 added to bone marrow monocytes during the differentiation stage. CONCLUSIONS:Our results suggest that RHcyst-1 is one of the major immunosuppressive proteins of BMDC function from blood-feeding ticks.

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Effect of Different Titanium Surfaces on Maturation of Murine Bone Marrow-Derived Dendritic Cells.

Project description:Dendritic cells (DCs) play a pivotal role in the host response to implanted biomaterials. Osseointegration of titanium (Ti) implant is an immunological and inflammatory-driven process. However, the role of DCs in this complex process is largely unknown. This study aimed to investigate the effect of different Ti surfaces on DC maturation, and evaluate its subsequent potential on osteogenic differentiation of preosteoblasts. Murine bone marrow-derived DCs were seeded on Ti disks with different surface treatments, including pretreatment (PT), sandblasted/acid-etched (SLA) and modified SLA (modSLA) surface. Compared with DCs cultured on PT and SLA surfaces, the cells seeded on modSLA surface demonstrated a more round morphology with lower expression of CD86 and MHC-II, the DC maturation markers. Those cells also secreted high levels of anti-inflammatory cytokine IL-10 and TGF-β. Notably, addition of conditioned medium (CM) from modSLA-induced DCs significantly increased the mRNA expression of Runx2 and ALP as well as ALP activity by murine preosteoblast MC3T3-E1 cells. Our data demonstrated that Ti disks with different surfaces lead to differential DCs responses. PT and SLA surfaces induce DCs mature, while DCs seeded on modSLA-Ti surface maintain an immature phenotype and exhibit a potential of promoting osteogenic differentiation of MC3T3-E1 cells.

| S-EPMC5291203 | biostudies-literature

Fibroblast growth factor 23 inhibits osteogenic differentiation and mineralization of chicken bone marrow mesenchymal stem cells.

Project description:Fibroblast growth factor 23 (FGF23), a bone-derived hormone, is involved in the reabsorption of phosphate (P) and the production of vitamin D hormones in the kidney. However, whether and how FGF23 regulates chicken bone metabolism remains largely unknown. In the present study, we investigated the effect of FGF23 on osteogenic differentiation and mineralization of chicken bone marrow mesenchymal stem cells (BMSCs). First, we found that the transcription of FGF23 was inhibited by β-glycerophosphate sodium (GPS, 5 mM, 10 mM, 20 mM) and 10-9 M 1, 25-dihydroxyvitamin D3 (1, 25(OH)2D3), but was stimulated by 10-7 M 1, 25(OH)2D3 and parathyroid hormone (PTH, 10-9 M, 10-8 M, 10-7 M). Second, overexpression of FGF23 by the FGF23 adenovirus (Adv-FGF23) suppressed the formation of mineralized nodules (P < 0.001) and alkaline phosphatase (ALP) activity (P < 0.05) in both differentiated and mineralized osteoblasts. Administration of FGF receptor 3 (FGFR3) inhibitor (50 nM) was sufficient to restore the FGF23-decreased ALP activity (P < 0.05), but not for the formation of mineralized nodules. In addition, the phosphorylation of ERK increased considerably with Adv-FGF23 overexpression (P < 0.05). Administration of an ERK-specific inhibitor (10 μM) could down-regulate the phosphorylation of ERK (P-ERK) (P < 0.05) and slightly restored the Adv-FGF23-reduction of ALP activity (P = 0.08). In summary, our data suggest that GPS, 1, 25(OH)2D3, and PTH could regulate FGF23 mRNA expression in vitro. FGF23 is a negative regulator of bone remodeling. FGF23 not only inhibits BMSCs osteogenesis through the FGFR3-ERK signaling pathway but also suppresses the mineralization of mature osteoblasts.

| S-EPMC9706642 | biostudies-literature

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