The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis

Jia, Xiaoyi; Cao, Yan; Sun, Xiaojing; Dai, Xing; Wei, Wei

doi:10.1016/j.intimp.2014.08.024

Cited by 32 publications

(21 citation statements)

References 91 publications

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“…In addition, our data on T cell polarization did not show any differences regarding Th1 (IFN-g + ) differentiation. We hypothesized that the significant increase in Th1/Th17 population could be related to the fact that EP 4 signaling increases IL-23 production [49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2

Flórez‐Grau

Cabezón

Borgman

et al. 2017

Journal of Leukocyte Biology

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Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE, produced during inflammation, has a pivotal role in the maturation of DCs and, therefore, is vital for the immune response. The large variety of biologic functions governed by PGE is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP and EP, which mediate the PGE signaling. However, the expression and function of EP receptors in human tolerogenic DCs (tol-DCs), which present an inhibitory phenotype, have not yet, to our knowledge, been assessed. To clarify the role of EP receptors in tol-DCs, we examined the expression of different EP receptors and their effect using selective agonists in human cells. We find that EP and EP expression are up-regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP-EP has a direct effect on the surface expression of costimulatory molecules and maturation receptors, such as CD80, CD83, and CD86 or MHCII and CCR7 in tol-DCs, the latter being exclusively modulated by PGE-EP signaling. Importantly, we find that EP and EP receptors are involved in tolerance induction through IL-10 production by tol-DCs. These results are in sharp contrast with the inflammatory role of EP Moreover, we show that DCs generated in the presence of agonists for EP receptors, induce naive T cell differentiation toward polarized Th1/Th17 cells. Given the differential effects of EP receptors, our results suggest that EP receptor agonist/antagonists might become relevant novel drug templates to modulate immune response.

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Section: Discussionmentioning

confidence: 99%

Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2

Flórez‐Grau

Cabezón

Borgman

et al. 2017

Journal of Leukocyte Biology

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“…PGE 2 dilates blood vessels and induces alterations in second messenger level via autocrine/paracrine signaling (34). Jia et al (35) identified that PGE 2 receptors present in arthritic tissue may combine with PGE 2 , and subsequently induce cartilage degradation, glycosaminoglycan loss and collagen type II degradation in OA animal models. However, these pathological changes can be alleviated in PGE 2 receptor knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Corticosterone suppresses IL-1β-induced mPGE2 expression through regulation of the 11β-HSD1 bioactivity of synovial fibroblasts in vitro

Wei

Zhu

Xiang

et al. 2017

Experimental and Therapeutic Medicine

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The aim of the present study was to investigate the correlation between glucocorticoid activity regulation, prostaglandin E2 (PGE2) synthesis, and synovial inflammation inhibition activity, through microsomal prostaglandin E synthase-1 (mPGES-1) expression regulated by the glucocorticoid pre-receptor regulator, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1). In the present study, fibroblast-like synovial cells of rats were studied as a cell model. Cells were stimulated with 10 ng/ml interleukin (IL)-1β for 24 h, and were subsequently, within the next 24 h, treated with or without 10−6 mmol/l corticosterone alone or with 100 nmol/l PF915275. At the end of the second 24 h, PGE2 levels in culture supernatants were assayed. Cells were harvested for mRNA evaluation of 11β-HSD1, mPGES-1, IL-1β and tumor necrosis factor (TNF)-α, and protein detection of 11β-HSD1 and mPGES-1 using reverse transcription-qualitative polymerase chain reaction and western blot analysis, respectively. Corticosterone was demonstrated to suppress the mRNA expression levels of inflammatory factors, such as TNF-α and PGE2, induced by IL-1β in vitro. Simultaneously, expression levels of 11β-HSD1 decreased significantly at the mRNA and protein levels (P<0.05). Cortisol concentration in the medium of the group treated with corticosterone was significantly increased (P<0.05) compared with that of the control group; however, the cortisol concentration was decreased in the medium when the conversion bioactivity of 11β-HSD1 was inhibited by PF915275, while the changes in 11β-HSD1 and mPGES-1 mRNA expression levels and PGE2 content were reversed in the medium. These results indicated that a significant positive correlation (P<0.01) may exist between mRNA and protein expression levels. To conclude, 11β-HSD1 is a key regulator for the synthesis of mPGES-1 and PGE2 in the inflammatory synovial cells in vitro, suggesting a potential interference target for osteoarthritis.

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“…This apparent discrepancy can be explained by the fact that, in the first system, PGE2 inhibits the APC release of IL-12, a required Th1 differentiation factor, whereas in the second system which includes exogenous IL-12, PGE2 upregulates the expression of IL-12Rβ2 in differentiating Th1 cells (31). The pro-inflammatory role of PGE2 has been confirmed in vivo in models of contact hypersensitivity, inflammatory bowel disease, rheumatoid arthritis, and experimental autoimmune encephalomyelitis (EAE), and shown to be mostly associated with increases in Th1/Th17 differentiation and/or function (18, 19, 32, 33). …”

Section: Introductionmentioning

confidence: 97%

Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1

Hooper

Yen

Kong

et al. 2017

The Journal of Immunology

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IL-27, a multifunctional cytokine produced by antigen-presenting cells, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well-studied, much less is known about the factors that negatively impact IL-27 expression. Prostaglandin E2 (PGE2), a major immunomodulatory prostanoid, acts as a pro-inflammatory agent in several models of inflammatory/autoimmune diseases, promoting primarily Th17 development and function. In this study, we report on a novel mechanism which promotes the pro-inflammatory function of PGE2. We showed previously that PGE2 inhibits IL-27 production in murine bone marrow derived DCs. Here, we show that, in addition to BMDCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IRF1 expression and binding to the p28 ISRE site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFNβ, STAT1 or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, EPAC, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo pro-inflammatory functions.

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The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis

Cited by 32 publications

References 91 publications

Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2

Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2

Corticosterone suppresses IL-1β-induced mPGE2 expression through regulation of the 11β-HSD1 bioactivity of synovial fibroblasts in vitro

Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1

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