CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis.
Animals
Ankle Joint
/ pathology
Antirheumatic Agents
/ therapeutic use
Arthritis, Experimental
/ drug therapy
Arthritis, Rheumatoid
/ drug therapy
Cell Proliferation
/ drug effects
Dinoprostone
/ metabolism
G-Protein-Coupled Receptor Kinase 2
/ genetics
Gene Knockdown Techniques
Glucosides
/ therapeutic use
Male
Monoterpenes
/ therapeutic use
Rats, Sprague-Dawley
Receptors, Prostaglandin E, EP4 Subtype
/ metabolism
Synoviocytes
/ drug effects
G protein-coupled receptor kinase 2
adjuvant-induced arthritis
fibroblast-like synoviocytes
paeoniflorin-6’-O-benzene sulfonate
prostaglandin E2
Journal
Acta pharmacologica Sinica
ISSN: 1745-7254
Titre abrégé: Acta Pharmacol Sin
Pays: United States
ID NLM: 100956087
Informations de publication
Date de publication:
Aug 2019
Aug 2019
Historique:
received:
12
07
2018
accepted:
13
11
2018
pubmed:
16
1
2019
medline:
24
12
2019
entrez:
16
1
2019
Statut:
ppublish
Résumé
Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel compound derived from paeoniflorin that has been demonstrated to have therapeutic effects in a rat model of rheumatoid arthritis (RA). However, the underlying mechanism has not been elucidated to date. We explored this mechanism in the present study by treating rats with adjuvant arthritis (AA) with CP-25. We found that the membrane EP4 protein level was downregulated; whereas, GRK2 was upregulated, in fibroblast-like synoviocyte (FLS)s of AA rats. Prostaglandin (PGE)2 stimulated FLS proliferation and enhanced the membrane EP4 receptor protein level; the latter was reversed by the administration of an EP4 receptor agonist, whereas the membrane GRK2 protein level gradually increased. The changes in the EP4 receptor and GRK2 expression were enhanced by TNF-α, and the former was accompanied by an alteration in the cyclic (c)AMP level. The EP4 receptor agonist stimulation increased the association between GRK2 and the EP4 receptor. GRK2 knockdown abrogated the abnormalities in FLS proliferation. The CP-25 treatment (100 mg/kg) suppressed joint inflammation with an efficacy that was similar to that of methotrexate. This finding was associated with EP4 upregulation and GRK2 downregulation in FLSs. Thus, GRK2 plays an important role in the abnormal FLS proliferation observed in AA possibly by promoting EP4 receptor desensitization and decreasing the cAMP level. Our results demonstrate that CP-25 has therapeutic potential for the treatment of human RA via GRK2 regulation.
Identifiants
pubmed: 30643209
doi: 10.1038/s41401-018-0196-2
pii: 10.1038/s41401-018-0196-2
pmc: PMC6786430
doi:
Substances chimiques
Antirheumatic Agents
0
Glucosides
0
Monoterpenes
0
Receptors, Prostaglandin E, EP4 Subtype
0
paeoniflorin-6'-O-benzenesulfonate
0
Grk2 protein, rat
EC 2.7.11.15
G-Protein-Coupled Receptor Kinase 2
EC 2.7.11.16
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1029-1039Références
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.
doi: 10.1038/nature01661
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.
doi: 10.1056/NEJMra1004965
Lefèvre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15:1414–20.
doi: 10.1038/nm.2050
Hillen J, Geyer C, Heitzmann M, Beckmann D, Krause A, Winkler I, et al. Structural cartilage damage attracts circulating rheumatoid arthritis synovial fibroblasts into affectedjoints. Arthritis Res Ther. 2017;19:40.
doi: 10.1186/s13075-017-1245-9
Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprintedaggressors. Nat Rev Rheumatol. 2013;9:24–33.
doi: 10.1038/nrrheum.2012.190
Kojima F, Naraba H, Sasaki Y, Beppu M, Aoki H, Kawai S. Prostaglandin E2 is an enhancer of interleukin-1beta-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts. Arthritis Rheum. 2003;48:2819–28.
doi: 10.1002/art.11261
Largo R, Díez-Ortego I, Sanchez-Pernaute O, López-Armada MJ, Alvarez-Soria MA, Egido J, et al. EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1beta in synovial fibroblasts. Ann Rheum Dis. 2004;63:1197–204.
doi: 10.1136/ard.2003.011163
Mitchell JA, Warner TD. Cyclo-oxygenase-2: pharmacology, physiology, iochemistry and relevance to NSAID therapy. Br J Pharmacol. 1999;128:1121–32.
doi: 10.1038/sj.bjp.0702897
Edwards JE, McQuay HJ, Moore RA. Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Pain. 2004;111:286–96.
doi: 10.1016/j.pain.2004.07.004
Xu M, Liu L, Qi C, Deng B, Cai X. Sinomenine versus NSAIDs for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Planta Med. 2008;74:1423–9.
doi: 10.1055/s-2008-1081346
Portanova JP, Zhang Y, Anderson GD, Hauser SD, Masferrer JL, Seibert K, et al. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J Exp Med. 1996;184:883–91.
doi: 10.1084/jem.184.3.883
Shi J, Johansson J, Woodling NS, Wang Q, Montine TJ, Andreasson K. The prostaglandin E2 E-prostanoid 4 receptor exerts anti-inflammatory effects in brain innate immunity. J Immunol. 2010;184:7207–18.
doi: 10.4049/jimmunol.0903487
Moriuchi-Murakami E, Yamada H, Ishii O, Kikukawa T, Igarashi R. Treatment of established collagen induced arthritis with prostaglandin E1 incorporated in lipid microspheres. J Rheumatol. 2000;27:2389–96.
pubmed: 11036835
Omote K, Kawamata T, Nakayama Y, Yamamoto H, Kawamata M, Namiki A. Effects of a novel selective agonist for prostaglandin receptor subtype EP4 on hyperalgesia and inflammation in monoarthritic model. Anesthesiology. 2002;97:170–6.
doi: 10.1097/00000542-200207000-00024
Shibata-Nozaki T, Ito H, Mitomi H, Akaogi J, Komagata T, Kanaji T, et al. Endogenous prostaglandin E2 inhibits aberrant overgrowth of rheumatoid synovial tissue and the development of osteoclast activity through EP4 receptor. Arthritis Rheum. 2011;63:2595–605.
doi: 10.1002/art.30428
Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001;53:1–24.
Chen Q, Wei W. Effects and mechanisms of glucosides of chaenomeles speciosa on collagen-induced arthritis in rats. Int Immunopharmacol. 2003;3:593–608.
doi: 10.1016/S1567-5769(03)00051-1
Xu HM, Wei W, Jia XY, Chang Y, Zhang L. Effects and mechanisms of total glucosides of paeony on adjuvant arthritis in rats. J Ethnopharmacol. 2007;109:442–8.
doi: 10.1016/j.jep.2006.08.019
Chen JY, Wu HX, Chen Y, Zhang LL, Wang QT, Sun WY, et al. Paeoniflorin inhibits proliferation of fibroblast-like synoviocytes through suppressing G-protein-coupled receptor kinase 2. Planta Med. 2012;78:665–71.
doi: 10.1055/s-0031-1298327
Chang Y, Jia X, Wei F, Wang C, Sun X, Xu S, et al. CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage. Sci Rep. 2016;6:26239.
doi: 10.1038/srep26239
Chen JY, Wang Y, Wu HX, Yan SX, Chang Y, Wei WA modified compound from paeoniflorin, CP-25, suppressed immune responses and synovium inflammation in collagen-induced arthritis mice. Front Pharmacol. Published: 07 June 2018 https://doi.org/10.3389/fphar.2018.00563
Jia X, Wei F, Sun X, Chang Y, Xu S, Yang X, et al. CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured with BAFF-activated CD4(+) T cells. J Ethnopharmacol. 2016;189:194–201.
doi: 10.1016/j.jep.2016.05.034
Li Y, Sheng K, Chen J, Wu Y, Zhang F, Chang Y, et al. Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25. Eur J Pharmacol. 2015;769:8–21.
doi: 10.1016/j.ejphar.2015.09.036
Chang Y, Wu Y, Wang D, Wei W, Qin Q, Xie G, et al. Therapeutic effects of TACI-Ig on rats with adjuvant-induced arthritis via attenuating inflammatory responses. Rheumatology. 2011;50:862–70.
doi: 10.1093/rheumatology/keq404
Wu H, Chen J, Song S, Yuan P, Liu L, Zhang Y, et al. β2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats. Sci Rep. 2016;6:24548.
doi: 10.1038/srep24548
Chen Y, Long H, Wu Z, Jiang X, Ma L. EGF transregulates opioid receptors through EGFR-mediated GRK2 phosphorylation and activation. Mol Biol Cell. 2008;19:2973–83.
doi: 10.1091/mbc.e07-10-1058
McCoy JM, Wicks JR, Audoly LP. The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest. 2002;110:651–8.
doi: 10.1172/JCI0215528
Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum. 2003;33:155–67.
doi: 10.1016/S0049-0172(03)00134-3
Wei W. Soft regulation of inflammatory immune responses. Chin Pharmacol Bull. 2016;32:297–303.
Nishigaki N, Negishi M, Ichikawa A. Two Gs-coupled prostaglandin E receptor subtypes, EP2 and EP4, differ in desensitization and sensitivity to the metabolic inactivation of the agonist. Mol Pharmacol. 1996;50:1031–7.
pubmed: 8863851
Neuschäfer-Rube F, Hänecke K, Püschel GP. The C-terminal domain of the human EP4 receptor confers agonist-induced receptor desensitization in a receptor hybrid with the rat EP3beta receptor. FEBS Lett. 1997;415:119–24.
doi: 10.1016/S0014-5793(97)01105-8
Neuschäfer-Rube F, Oppermann M, Möller U, Böer U, Püschel GP. Agonist-induced phosphorylation by G protein-coupled receptor kinases of the EP4 receptor carboxyl-terminal domain in an EP3/EP4 prostaglandin E(2) receptor hybrid. Mol Pharmacol. 1999;56:419–28.
doi: 10.1124/mol.56.2.419
Bastepe M, Ashby B. Identification of a region of the C-terminal domain involved in short-term desensitization of the prostaglandin EP4 receptor. Br J Pharmacol. 1999;126:365–71.
doi: 10.1038/sj.bjp.0702291
Shukla AK, Xiao K, Lefkowitz RJ. Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem Sci. 2011;36:457–69.
doi: 10.1016/j.tibs.2011.06.003
Beautrait A, Michalski KR, Lopez TS, Mannix KM, McDonald DJ, Cutter AR, et al. Mapping the putative G protein-coupled receptor (GPCR) docking site on GPCR kinase 2: insights from intact cell phosphorylation and recruitment assays. J Biol Chem. 2014;289:25262–75.
doi: 10.1074/jbc.M114.593178
Tian X, Kang DS, Benovic JL. β-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol. 2014;219:173–86.
doi: 10.1007/978-3-642-41199-1_9
Lorton D, Bellinger DL, Schaller JA, Shewmaker E, Osredkar T, Lubahn C. Altered sympathetic-to-immune cell signaling via β-adrenergic receptors in adjuvant arthritis. Clin Dev Immunol. 2013; 2013:764395.
Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509.
doi: 10.1136/annrheumdis-2013-204573
Wang Y, Han CC, Cui D, Luo TT, Li Y, Zhang Y, et al. Immunomodulatory effects of CP-25 on splenic T cells of rats with adjuvant arthritis. Inflammation. 2018;41:1049–63.
doi: 10.1007/s10753-018-0757-z