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Regulatory effects of paeoniflorin-6′-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats

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Abstract

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6′-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.

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Abbreviations

AA:

Rat adjuvant-induced arthritis

BMDCs:

Bone marrow-derived DCs

CFA:

Complete Freund’s adjuvant

CP-25:

Paeoniflorin-6′-O-benzene sulfonate

DC:

Dendritic cell

DMAR:

Disease-modifying antirheumatic drugs

ELISA:

Enzyme-linked immunosorbent assay

FCS:

Fetal calf serum

MLR:

Mixed lymphocyte reaction;

MTX:

Methotrexate

Pae:

Paeoniflorin

PGE2:

Prostaglandin E2

qRT-PCR:

Quantification via real-time PCR

RA:

Rheumatoid arthritis

TNFα:

Tumor necrosis factor-α

TGP:

Total glucosides of peony

References

  • Aghdami N, Gharibdoost F, Moazzeni SM (2008) Experimental autoimmune encephalomyelitis (EAE) induced by antigen pulsed dendritic cells in the C57BL/6 mouse: Influence of injection route. Exp Anim 57:45–55

    Article  CAS  Google Scholar 

  • Ahmed MS, Bae YS (2016) Dendritic Cell-based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside. Immune Netw 16:44–51

    Article  Google Scholar 

  • Balanescu A, Nat R, Regalia T, Radu E, Bojinca V, Ionescu R, Predescu V, Popescu E, Predeţeanu D (2003) Correlation between the immunophenotypical presentation of dendritic cells and the clinical response to anti-rheumatic treatment in rheumatoid arthritis. Rom J Intern Med 41:255–267

    PubMed  Google Scholar 

  • Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  CAS  Google Scholar 

  • Chang Y, Jia X, Wei F, Wang C, Sun X, Xu S, Yang X, Zhao Y, Chen J, Wu H, Zhang L, Wei W (2016) CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage. Sci Rep 6:26239

    Article  CAS  Google Scholar 

  • Chen J, Wang Y, Wu H, Yan S, Chang Y, Wei W (2018) A modified compound from paeoniflorin, CP-25, suppressed immune responses and synovium inflammation in collagen-induced arthritis mice. Front Pharmacol 9:563

    Article  Google Scholar 

  • Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Natur 423:356–361

    Article  CAS  Google Scholar 

  • Flores-Borja F, Mauri C, Ehrenstein MR (2008) Restoring the balance: harnessing regulatory T cells for therapy in rheumatoid arthritis. Eur J Immunol 38:934–937

    Article  CAS  Google Scholar 

  • Grauer O, Wohlleben G, Seubert S, Weishaupt A, Kämpgen E, Gold R (2002) Analysis of maturation states of rat bone marrow-derived dendritic cells using an improved culture technique. Histochem Cell Biol 117:351–362

    Article  CAS  Google Scholar 

  • Hackstein H, Thomson AW (2004) Dendritic cells: Emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol 4:24–34

    Article  CAS  Google Scholar 

  • Harizi H, Grosset C, Gualde N (2003) Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes. J Leukoc Biol 73:756–763

    Article  CAS  Google Scholar 

  • Hayashi S, Miura Y, Tateishi K, Takahashi M, Kurosaka M (2010) Decoy receptor 3 is highly expressed in patients with rheumatoid arthritis. Mod Rheumatol 20:63–68

    Article  CAS  Google Scholar 

  • Van Helden SF, Krooshoop DJ, Broers KC, Raymakers RA, Figdor CG, van Leeuwen FN (2006) A critical role for prostaglandin E2 in podosome dissolution and induction of highspeed migration during dendritic cell maturation. J Immunol 177:1567–1574

    Article  Google Scholar 

  • Honda T, Segi-Nishida E, Miyachi Y, Narumiya S (2006) Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. J Exp Med 203:325–335

    Article  CAS  Google Scholar 

  • Jia XY, Chang Y, Sun XJ, Dai X, Wei W (2014) The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis. Int Immunopharmacol 23:163–169

    Article  CAS  Google Scholar 

  • Jia X, Wei F, Sun X, Chang Y, Xu S, Yang X, Wang C, Wei W (2016) CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured with BAFF-activated CD4(+) T cells. J Ethnopharmacol 189:194–201

    Article  CAS  Google Scholar 

  • Jia XY, Chang Y, Wei F, Dai X, Wu YJ, Sun XJ, Xu S, Wu HX, Wang C, Yang XZ, Wei W (2019) CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-018-0196-2

    Article  CAS  Google Scholar 

  • Jiang GL, Nieves A, Im WB, Old DW, Dinh DT, Wheeler L (2007) The prevention of colitis by E Prostanoid receptor 4 agonist through enhancement of epithelium survival and regeneration. Pharmaol Exp Ther 320:22–28

    Article  CAS  Google Scholar 

  • Khayrullina T, Yen JH, Jing H, Ganea D (2008) In vitro differentiation of dendritic cells in the presence of prostaglandin E2 alters the IL-12/IL-23 balance and promotes differentiation of Th17 cells. J Immunol 181:721–735

    Article  CAS  Google Scholar 

  • Klareskog L, Catrina A, Paget S (2009) Rheumatoid arthritis. Lancet 373:659–672

    Article  CAS  Google Scholar 

  • Lebre MC, Jongbloed SL, Tas SW, Smeets TJ, McInnes IB, Tak PP (2008) Rheumatoid arthritis synovium contains two subsets of CD83-DC-LAMP- dendritic cells with distinct cytokine profiles. Am J Pathol 172:940–950

    Article  CAS  Google Scholar 

  • Liu Y, Wang S, Shen L, Xu Y (2010) Effects of simvastatin on the function of dendritic cells in patients with rheumatic arthritis. J Huazhong Univ Sci Technol Med Sci 30:741–745

    Article  CAS  Google Scholar 

  • Martel-Pelletier J, Pelletier JP, Fahmi H (2003) Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum 33:155–167

    Article  CAS  Google Scholar 

  • McCoy JM, Wicks JR, Audoly LP (2002) The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest 110:651–658

    Article  CAS  Google Scholar 

  • Rieser C, Böck G, Klocker H, Bartsch G, Thurnher M (1997) Prostaglandin E2 and tumor necrosis factor a cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production. J Exp Med 186:1603–1608

    Article  CAS  Google Scholar 

  • Sallusto F, Cella M, Danieli C, Lanzavecchia A (1995) Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med 182:389–400

    Article  CAS  Google Scholar 

  • Santiago-Schwarz F, Anand P, Liu S, Carsons SE (2001) Dendritic cells (DCs) in rheumatoid arthritis (RA): progenitor cells and soluble factors contained in RA synovial fluid yield a subset of myeloid DCs that preferentially activate Th1 inflammatory-type responses. J Immunol 167:1758–1768

    Article  CAS  Google Scholar 

  • Sarkar S, Fox DA (2005) Dendritic cells in rheumatoid arthritis. Front Biosci 10:656–665

    Article  CAS  Google Scholar 

  • Schirmer C, Klein C, von Bergen M, Simon JC, Saalbach A (2010) Human fibroblasts support the expansion of IL-17-producing T cells via up-regulation of IL-23 production by dendritic cells. Blood 16:1715–1725

    Article  Google Scholar 

  • Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 376:1094–1108

    Article  Google Scholar 

  • Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D (2004) Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. FASEB J 18:1318–1320

    Article  CAS  Google Scholar 

  • Singh P, Hoggatt J, Hu P, Speth JM, Fukuda S, Breyer RM, Pelus LM (2012) Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells. Blood 119:1671–1682

    Article  CAS  Google Scholar 

  • Swart JF, Wulffraat NM (2014) Mesenchymal stromal cells for treatment of arthritis. Best Pract Res Clin Rheumatol 28:589–603

    Article  CAS  Google Scholar 

  • Thomas R, MacDonald KP, Pettit AR, Cavanagh LL, Padmanabha J, Zehntner S (1999) Dendritic cells and the pathogenesis of rheumatoid arthritis. J Leukoc Biol 66:286–292

    Article  CAS  Google Scholar 

  • Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, Pandher K, Lapointe JM, Saha S, Roach ML, Carter D, Thomas NA, Durtschi BA, McNeish JD, Hambor JE, Jakobsson PJ, Carty TJ, Perez JR, Audoly LP (2003) Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci USA 100:9044–9049

    Article  CAS  Google Scholar 

  • Vassiliou E, Jing H, Ganea D (2003) Prostaglandin E2 inhibits TNF-α production in murine bone marrow-derived dendritic cells. Cell Immunol 223:120–132

    Article  CAS  Google Scholar 

  • Wang Y, Han CC, Cui D, Luo TT, Li Y, Zhang Y, Ma Y, Wei W (2018) Immunomodulatory effects of CP-25 on splenic T cells of rats with adjuvant arthritis. Inflammation 41:1049–1063

    Article  CAS  Google Scholar 

  • Wu H, Chen J, Song S, Yuan P, Liu L, Zhang Y, Zhou A, Chang Y, Zhang L, Wei W (2016) β2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats. Sci Rep 6:24548

    Article  CAS  Google Scholar 

  • Wu YJ, Chen HS, Chen WS, Dong J, Dong XJ, Dai X, Huang Q, Wei W (2018) CP-25 Attenuates the Activation of CD4(+) T Cells Stimulated with Immunoglobulin D in Human. Front Pharmacol 9:4

    Article  Google Scholar 

  • Yamazaki S, Inaba K, Tarbell KV, Steinman RM (2006) Dendritic cells expand antigen-specific Foxp3+CD25+CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev 212:314–329

    Article  CAS  Google Scholar 

  • Yang L, Yamagata N, Yadav R, Brandon S, Courtney RL, Morrow JD, Shyr Y, Boothby M, Joyce S, Carbone DP, Breyer RM (2003) Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest 111:727–735

    Article  CAS  Google Scholar 

  • Yang X, Zhao Y, Jia X, Wang C, Wu Y, Zhang L, Chang Y, Wei W (2019) CP-25 combined with MTX/LEF ameliorates the progression of adjuvant-induced arthritis by the inhibition on GRK2 translocation. Biomed Pharmacother 110:834–843

    Article  CAS  Google Scholar 

  • Yen JH, Kocieda VP, Jing H, Ganea D (2011) Prostaglandin E2 induces matrix metalloproteinase 9 expression in dendritic cells through two independent signaling pathways leading to activator protein 1 (AP-1) activation. J Biol Chem 286:38913–38923

    Article  CAS  Google Scholar 

  • Zhang F, Shu JL, Li Y, Wu YJ, Zhang XZ, Han L, Tang XY, Wang C, Wang QT, Chen JY, Chang Y, Wu HX, Zhang LL, Wei W (2017) CP-25, a novel anti-inflammatory and immunomodulatory drug, inhibits the functions of activated human B cells through regulating BAFF and TNF-alpha signaling and comparative efficacy with biological agents. Front Pharmacol 8:933

    Article  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81330081, 31200675, 81573443, 81603362), by the Anhui Province Nature Science Foundation in the University (KJ2015A317), by Anhui Province Natural Science Fund (outstanding youth) (170808J10).

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Authors and Affiliations

  1. Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China

    Xiao-yi Jia, Yan Chang, Xiao-jing Sun, Fang Wei, Yu-jing Wu, Xing Dai, Shu Xu, Hua-xun Wu, Chun Wang, Xue-zhi Yang & Wei Wei

  2. School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China

    Xiao-yi Jia

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  1. Xiao-yi Jia
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Contributions

WW and YC conceived and designed the study. XYJ designed and performed most of the experiments, and wrote the manuscript. FW, XD, XJS, SX and XZY performed experiments. YJW carried out the flow cytometry assays and helped to revise the manuscript. HXW and CW participated in the design of the study and helped to revise the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wei Wei.

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Jia, Xy., Chang, Y., Sun, Xj. et al. Regulatory effects of paeoniflorin-6′-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats. Inflammopharmacol 27, 997–1010 (2019). https://doi.org/10.1007/s10787-019-00575-8

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