Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes

Abstract

Our previous study showed that chronic treatment with tumor necrosis factor-α (TNF-α) decreased cAMP concentration in fibroblast-like synoviocytes (FLSs) of collagen-induced arthritis (CIA) rats. In this study we investigated how TNF-α impairs cAMP homeostasis, particularly clarifying the potential downstream molecules of TNF-α and prostaglandin receptor 4 (EP4) signaling that would interact with each other. Using a cAMP FRET biosensor PM-ICUE3, we demonstrated that TNF-α (20 ng/mL) blocked ONO-4819-triggered EP4 signaling, but not Butaprost-triggered EP2 signaling in normal rat FLSs. We showed that TNF-α (0.02–20 ng/mL) dose-dependently reduced EP4 membrane distribution in normal rat FLS. TNF-α significantly increased TNF receptor 2 (TNFR2) expression and stimulated proliferation in human FLS (hFLS) via ecruiting TNF receptor-associated factor 2 (TRAF2) to cell membrane. More interestingly, we revealed that TRAF2 interacted with G protein-coupled receptor kinase (GRK2) in the cytoplasm of primary hFLS and helped to bring GRK2 to cell membrane in response of TNF-α stimulation, the complex of TRAF2 and GRK2 then separated on the membrane, and translocated GRK2 induced the desensitization and internalization of EP4, leading to reduced production of intracellular cAMP. Silencing of TRAF2 by siRNA substantially diminished TRAF2-GRK2 interaction, blocked the translocation of GRK2, and resulted in upregulated expression of membrane EP4 and intracellular cAMP. In CIA rats, administration of paroxetine to inhibit GRK2 effectively improved the symptoms and clinic parameters with significantly reduced joint synovium inflammation and bone destruction. These results elucidate a novel form of cross-talk between TNFR (a cytokine receptor) and EP4 (a typical G protein-coupled receptor) signaling pathways. The interaction between TRAF2 and GRK2 may become a potential new drug target for the treatment of inflammatory diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: EP4 signaling is blocked in TNF-α-stimulated FLS.
Fig. 2: TNF-α impairs EP4 signaling in hFLSs in a TNFR2-dependent manner.
Fig. 3: TNF-α impairs EP4 signaling in hFLSs in a TNFR2- and TRAF2-dependent manner.
Fig. 4: TNF-α triggers the translocation of the TRAF2-GRK2 complex to the cell membrane and induces complex dissociation.
Fig. 5: Molecular docking of GRK2 and TRAF2.
Fig. 6: TRAF2 silencing reduces EP4 desensitization by decreasing membrane GRK2 translocation. Inhibition of GRK2 attenuates TNF-α-induced FLS proliferation.
Fig. 7: Paroxetine treatment attenuates the symptoms of CIA rats.
Fig. 8: Potential mechanisms of TNF-α-mediated EP4 signaling.

References

  1. 1.

    Dayer JM. From supernatants to cytokines: a personal view on the early history of IL-1, IL-1Ra, TNF and its inhibitor in rheumatology. Arthritis Res Ther. 2018;20:101.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Ursini F, Leporini C, Bene F, D’Angelo S, Mauro D, Russo E, et al. Anti-TNF-alpha agents and endothelial function in rheumatoid arthritis: a systematic review and meta-analysis. Sci Rep. 2017;7:5346.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Jia XY, Chang Y, Sun XJ, Dai X, Wei W. The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis. Int Immunopharmacol. 2014;23:163–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Samuels JS, Holland L, Lopez M, Meyers K, Cumbie WG, McClain A, et al. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRgamma pathways to initiate Th17 CD4+ T-cell development during rheumatoid arthritis. Inflamm Res. 2018;67:589–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Lowin T, Apitz M, Anders S, Straub RH. Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner. Arthritis Res Ther. 2015;17:321.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Li H, Chen HY, Liu WX, Jia XX, Zhang JG, Ma CL, et al. Prostaglandin E2 restrains human Treg cell differentiation via E prostanoid receptor 2-protein kinase A signaling. Immunol Lett. 2017;191:63–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Frolov A, Yang L, Dong H, Hammock BD, Crofford LJ. Anti-inflammatory properties of prostaglandin E2: deletion of microsomal prostaglandin E synthase-1 exacerbates non-immune inflammatory arthritis in mice. Prostaglandins Leukot Ess Fat Acids. 2013;89:351–8.

    CAS  Article  Google Scholar 

  8. 8.

    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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Treutlein EM, Kern K, Weigert A, Tarighi N, Schuh CD, Nusing RM, et al. The prostaglandin E2 receptor EP3 controls CC-chemokine ligand 2-mediated neuropathic pain induced by mechanical nerve damage. J Biol Chem. 2018;293:9685–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Kawashima M, Ogura N, Akutsu M, Ito K, Kondoh T. The anti-inflammatory effect of cyclooxygenase inhibitors in fibroblast-like synoviocytes from the human temporomandibular joint results from the suppression of PGE2 production. J Oral Pathol Med. 2013;42:499–506.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Vitali E, Cambiaghi V, Spada A, Tresoldi A, Zerbi A, Peverelli E, et al. cAMP effects in neuroendocrine tumors: The role of Epac and PKA in cell proliferation and adhesion. Exp Cell Res. 2015;339:241–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Liu D, Huang Y, Bu D, Liu AD, Holmberg L, Jia Y, et al. Sulfur dioxide inhibits vascular smooth muscle cell proliferation via suppressing the Erk/MAP kinase pathway mediated by cAMP/PKA signaling. Cell Death Dis. 2014;5:e1251.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Uemura Y, Shibata R, Ohashi K, Enomoto T, Kambara T, Yamamoto T, et al. Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J. 2013;27:25–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Xie J, Ponuwei GA, Moore CE, Willars GB, Tee AR, Herbert TP. cAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity. Cell Signal. 2011;23:1927–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Sun L, Zhao R, Zhang L, Zhang W, He G, Yang S, et al. Prevention of vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia by CREB-mediated p21 induction: an insight from a plant polyphenol. Biochem Pharmacol. 2016;103:40–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Park ES, Choi S, Shin B, Yu J, Yu J, Hwang JM, et al. Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction. J Biol Chem. 2015;290:9660–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Chang Y, Wei W, Zhang L, Xu HM. Effects and mechanisms of total glucosides of paeony on synoviocytes activities in rat collagen-induced arthritis. J Ethnopharmacol. 2009;121:43–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Wang QT, Zhang LL, Wu HX, Wei W. The expression change of beta-arrestins in fibroblast-like synoviocytes from rats with collagen-induced arthritis and the effect of total glucosides of paeony. J Ethnopharmacol. 2011;133:511–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Huang B, Wang QT, Song SS, Wu YJ, Ma YK, Zhang LL, et al. Combined use of etanercept and MTX restores CD4+/CD8+ ratio and Tregs in spleen and thymus in collagen-induced arthritis. Inflamm Res. 2012;61:1229–39.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Nair A, Kanda V, Bush-Joseph C, Verma N, Chubinskaya S, Mikecz K, et al. Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14. Arthritis Rheum. 2012;64:2268–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Lane JR, Beukers MW, Mulder-Krieger T, Ijzerman AP. The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor. Biochem Pharmacol. 2010;79:48–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Sun Z, Runne C, Tang X, Lin F, Chen S. The Gbeta3 splice variant associated with the C825T gene polymorphism is an unstable and functionally inactive protein. Cell Signal. 2012;24:2349–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Han YS, Lan L, Chu J, Kang WQ, Ge ZM. Epigallocatechin gallate attenuated the activation of rat cardiac fibroblasts induced by angiotensin II via regulating beta-arrestin1. Cell Physiol Biochem. 2013;31:338–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Isono E, Schwechheimer C. Co-immunoprecipitation and protein blots. Methods Mol Biol. 2010;655:377–87.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Huang C, Dai X, Chai W. Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in. Cell Res. 2012;22:1681–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Foudi N, Kotelevets L, Louedec L, Leseche G, Henin D, Chastre E, et al. Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: role of the EP4 receptor subtype. Br J Pharmacol. 2008;154:1631–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Angiolilli C, Kabala PA, Grabiec AM, Rossato M, Lai WS, Fossati G, et al. Control of cytokine mRNA degradation by the histone deacetylase inhibitor ITF2357 in rheumatoid arthritis fibroblast-like synoviocytes: beyond transcriptional regulation. Arthritis Res Ther. 2018;20:148.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Wang H, Dong BW, Zheng ZH, Wu ZB, Li W, Ding J. Metastasis-associated protein 1 (MTA1) signaling in rheumatoid synovium: regulation of inflammatory response and cytokine-mediated production of prostaglandin E2 (PGE2). Biochem Biophys Res Commun. 2016;473:442–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Quistad SD, Traylor-Knowles N. Precambrian origins of the TNFR superfamily. Cell Death Discov. 2016;2:16058.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors. Cell Signal. 2012;24:1297–305.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Legler DF, Micheau O, Doucey MA, Tschopp J, Bron C. Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation. Immunity. 2003;18:655–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Lodowski DT, Barnhill JF, Pyskadlo RM, Ghirlando R, Sterne-Marr R, Tesmer JJ. The role of G beta gamma and domain interfaces in the activation of G protein-coupled receptor kinase 2. Biochemistry. 2005;44:6958–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Park HH. Structure of TRAF family: current understanding of receptor recognition. Front Immunol. 2018;9:1999.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, et al. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015;7:277ra231.

    Article  CAS  Google Scholar 

  35. 35.

    Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Youn J, Kim HY, Park JH, Hwang SH, Lee SY, Cho CS, et al. Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-kappaB in synoviocytes obtained from patients with rheumatoid arthritis. Immunol Lett. 2002;83:85–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    De Keijzer S, Meddens MB, Torensma R, Cambi A. The multiple faces of prostaglandin E2 G-protein coupled receptor signaling during the dendritic cell life cycle. Int J Mol Sci. 2013;14:6542–55.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Kunisch E, Jansen A, Kojima F, Loffler I, Kapoor M, Kawai S, et al. Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP. J Immunol. 2009;183:1328–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Woodward DF, Jones RL, Narumiya S. International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev. 2011;63:471–538.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Axelsson H, Lonnroth C, Andersson M, Lundholm K. Mechanisms behind COX-1 and COX-2 inhibition of tumor growth in vivo. Int J Oncol. 2010;37:1143–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lin WJ, Su YW, Lu YC, Hao Z, Chio II, Chen NJ, et al. Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunity. Proc Natl Acad Sci USA. 2011;108:18354–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Crunkhorn S. Inflammatory disorders: targeting TRAFs tames inflammation. Nat Rev Drug Discov. 2013;12:423.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Rodriguez M, Cabal-Hierro L, Carcedo MT, Iglesias JM, Artime N, Darnay BG, et al. NF-kappaB signal triggering and termination by tumor necrosis factor receptor 2. J Biol Chem. 2011;286:22814–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Kim S, Lewis C, Nadel JA. Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells. Exp Cell Res. 2011;317:2650–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature. 2010;465:1084–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Niedermeier M, Pap T, Korb A. Therapeutic opportunities in fibroblasts in inflammatory arthritis. Best Pr Res Clin Rheumatol. 2010;24:527–40.

    Article  Google Scholar 

  47. 47.

    Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233:233–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Doherty GA, Byrne SM, Molloy ES, Malhotra V, Austin SC, Kay EW, et al. Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer. BMC Cancer. 2009;9:207.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Murdaca G, Colombo BM, Cagnati P, Gulli R, Spano F, Puppo F. Update upon efficacy and safety of TNF-alpha inhibitors. Expert Opin Drug Saf. 2012;11:1–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Ehlers S. Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF. Ann Rheum Dis. 2003;62(Suppl 2):ii37–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Canete JD, Pablos JL. Biologic therapy in rheumatoid arthritis. Curr Top Med Chem. 2013;13:752–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Eijkelkamp N, Wang H, Garza-Carbajal A, Willemen HL, Zwartkruis FJ, Wood JN, et al. Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK. J Neurosci. 2010;30:12806–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El-Mays T, et al. beta-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci USA. 2012;109:16660–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Penn RB, Pascual RM, Kim YM, Mundell SJ, Krymskaya VP, Panettieri RA Jr., et al. Arrestin specificity for G protein-coupled receptors in human airway smooth muscle. J Biol Chem. 2001;276:32648–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Shi CS, Kehrl JH. Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). J Biol Chem. 2003;278:15429–34.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Liu H, Nishitoh H, Ichijo H, Kyriakis JM. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol. 2000;20:2198–208.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Kalsoom UE, Habib R, Khan B, Ali G, Ali N, Ansar M, et al. Mutations in lipase H gene underlie autosomal recessive hypotrichosis in five Pakistani families. Acta Derm Venereol. 2010;90:93–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Ke F, Zhang L, Liu Z, Yan S, Xu Z, Bai J, et al. Soluble tumor necrosis factor receptor 1 released by skin-derived mesenchymal stem cells is critical for inhibiting Th17 cell differentiation. Stem Cells Transl Med. 2016;5:301–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Wheeler MA, Heffner DL, Kim S, Espy SM, Spano AJ, Cleland CL, et al. TNF-alpha/TNFR1 signaling is required for the development and function of primary nociceptors. Neuron. 2014;82:587–602.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Evron T, Daigle TL, Caron MG. GRK2: multiple roles beyond G protein-coupled receptor desensitization. Trends Pharmacol Sci. 2012;33:154–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Vroon A, Heijnen CJ, Kavelaars A. GRKs and arrestins: regulators of migration and inflammation. J Leukoc Biol. 2006;80:1214–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Tarrant TK, Rampersad RR, Esserman D, Rothlein LR, Liu P, Premont RT, et al. Granulocyte chemotaxis and disease expression are differentially regulated by GRK subtype in an acute inflammatory arthritis model (K/BxN). Clin Immunol. 2008;129:115–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, et al. The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim Biophys Acta. 2007;1768:913–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Khanna D, Park GS, Paulus HE, Simpson KM, Elashoff D, Cohen SB, et al. Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis Rheum. 2005;52:3030–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81973332, 81973314, 81673444, 81330081 and 81202541), the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars (1808085J28), the Key Projects of Natural Science Research of Anhui Colleges and Universities (KJ2017A176), the Anhui University Excellent Youth Talent Support Program (gxyqZD2017025), the Innovation and Entrepreneurship Support Program for Returnees of Anhui Province (2017), The University Synergy Innovation Program of Anhui Province (GXXT-2020-066), the Program for Upgrading Scientific Research Level of Anhui Medical University (2019xkjT008), and the Program for Upgrading Basic and Clinical Collaborative Research of Anhui Medical University (2020xkjT033).

Author information

Affiliations

Authors

Contributions

YT, BH, PPG, ZW, ZWZ, MMW, HFS, YH, SLX and LLZ conducted the study and analyzed the data, YT, QTW and WW analyzed the data and wrote the paper.

Corresponding authors

Correspondence to Qing-tong Wang or Wei Wei.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tai, Y., Huang, B., Guo, Pp. et al. TNF-α impairs EP4 signaling through the association of TRAF2-GRK2 in primary fibroblast-like synoviocytes. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00654-z

Download citation

Keywords

  • rheumatoid arthritis
  • fibroblast-like synoviocytes
  • TNFR2
  • TRAF2
  • GRK2
  • EP4

Search

Quick links