Inflammation

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Immunomodulatory Effects of CP-25 on Splenic T Cells of Rats with Adjuvant Arthritis

ORIGINAL ARTICLE
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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease in which T cells play an important role. Paeoniflorin-6-oxy-benzenesulfonate (CP-25) shows a strong anti-inflammatory and immunomodulatory effect in the joint of adjuvant arthritis (AA) rats, but the role of the spleen function is still unclear. The aim of this study was to research how CP-25 regulated spleen function of AA rats. Male Sprague-Dawley rats were administered with CP-25 (50 mg/kg) orally from day 17 to 29 after immunization. The spleen histopathological changes were analyzed by hematoxylin–eosin staining. G protein-coupled receptor kinases (GRKs) and prostaglandin receptor subtypes (EPs) were screened by Western blot and immunohistochemistry. The co-expression of GRK2 and EP2 as well as GRK2 and EP4 was measured by immunofluorescence and co-immunoprecipitation. The expression of GRK2 and EP4 in splenic T cells was further detected by immunofluorescence. CP-25 was found to relieve the secondary paw swelling, attenuate histopathologic changes, and downregulate GRK2, EP2 and EP4 expression in AA rats. Additionally, CP-25 not only downregulated the co-expression of GRK2 and EP4 but also downregulated GRK2, EP4 expression in splenic T cells of AA rats. From these results, we can infer that CP-25 play an anti-inflammatory and immune function by affecting the function of the splenic T cells.

KEY WORDS

rheumatoid arthritis spleen G protein-coupled receptor kinases (GRKs) prostaglandin receptor subtypes (EPs) CP-25 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    López Mantecón, A.M., G. Garrido, R. Delgado-Hernández, and B.B. Garrido-Suárez. 2014. Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study. Phytotherapy Research 28 (8): 1163–1172.CrossRefPubMedGoogle Scholar
  2. 2.
    Zwerina, J., K. Redlich, G. Schett, and J.S. Smolen. 2005. Pathogenesis of rheumatoid arthritis: targeting cytokines. Annals of the New York Academy of Sciences: 716–729.Google Scholar
  3. 3.
    Zhang, X., T. Nakajima, J.J. Goronzy, and C.M. Weyand. 2005. Tissue trafficking patterns of effector memory CD4 + T cells in rheumatoid arthritis. Arthritis and Rheumatism 52 (12): 3839–3849.CrossRefPubMedGoogle Scholar
  4. 4.
    Rogers, J.L., D.S. Serafin, R.G. Timoshchenko, and T.K. Tarrant. 2012. Cellular targeting in autoimmunity. Current Allergy and Asthma Reports 12 (6): 495–510.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Martin, R. 2012. Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing-remitting multiple sclerosis. Clinical Immunology 142 (1): 9–14.CrossRefPubMedGoogle Scholar
  6. 6.
    Pierce, K.L., R.T. Premont, and R.J. Lefkowitz. 2002. Seven-transmembrane receptors. Nature Reviews. Molecular Cell Biology 3 (9): 639–650.CrossRefPubMedGoogle Scholar
  7. 7.
    Neumann, E., K. Khawaja, and U. Müller-Ladner. 2014. G protein-coupled receptors in rheumatology. Nature Reviews Rheumatology 10 (7): 429–436.CrossRefPubMedGoogle Scholar
  8. 8.
    Shukla, A.K., A. Manglik, A.C. Kruse, K. Xiao, R.I. Reis, W.C. Tseng, et al. 2013. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497 (7447): 137–141.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sato, P.Y., J.K. Chuprun, M. Schwartz, and W.J. Koch. 2015. The evolving impact of g protein-coupled receptor kinases in cardiac health and disease. Physiological Reviews 95 (2): 377–404.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen, C.K., K. Zhang, J. Church-Kopish, W. Huang, H. Zhang, Y.J. Chen, et al. 2001. Characterization of human GRK7 as a potential cone opsin kinase. Molecular Vision 7: 305–313.PubMedGoogle Scholar
  11. 11.
    Zeng, C., V.A. Villar, G.M. Eisner, S.M. Williams, R.A. Felder, et al. 2008. G protein-coupled receptor kinase 4: role in blood pressure regulation. Hypertension 51 (6): 1449–1455.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dautzenberg, F.M., S. Wille, S. Braun, and R.L. Hauger. 2002. GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization. Biochemical and Biophysical Research Communications 298 (3): 303–308.CrossRefPubMedGoogle Scholar
  13. 13.
    Schulz, R., A. Wehmeyer, and K. Schulz. 2002. Visualizing preference of G protein-coupled receptor kinase 3 for the process of kappa-opioid receptor sequestration. Molecular Pharmacology 61 (6): 1444–1452.CrossRefPubMedGoogle Scholar
  14. 14.
    Bawa, T., G.F. Altememi, D.C. Eikenburg, and K.M. Standifer. 2003. Desensitization of alpha 2A adrenoceptor signalling by modest levels of adrenaline is facilitated by beta 2-adrenoceptor-dependent GRK3 up-regulation. British Journal of Pharmacology 138 (5): 921–931.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Taneja, M., S. Salim, K. Saha, H.K. Happe, N. Qutna, F. Petty, et al. 2011. Differential effects of inescapable stress on locus coeruleus GRK3, alpha2-adrenoceptor and CRF1 receptor levels in learned helpless and non-helpless rats: a potential link to stress resilience. Behavioural Brain Research 221 (1): 25–33.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Belmonte, S.L., and B.C. Blaxall. 2011. G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circulation Research 109 (3): 309–319.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gainetdinov, R.R., R.T. Premont, M.G. Caron, and R.J. Lefkowitz. 2000. Reply: receptor specificity of G-protein-coupled receptor kinases. Trends in Pharmacological Sciences 21 (10): 366–367.CrossRefPubMedGoogle Scholar
  18. 18.
    Breye, M.D., and R.M. Breyer. 2000. Prostaglandin E receptors and the kidney. American Journal of Physiology. Renal Physiology 279 (1): F12–F23.CrossRefGoogle Scholar
  19. 19.
    Tsuboi, K., Y. Sugimoto, and A. Ichikawa. 2002. Prostanoid receptor subtypes. Prostaglandins & Other Lipid Mediators 68-69: 535–556.CrossRefGoogle Scholar
  20. 20.
    Kunisch, E., A. Jansen, F. Kojima, I. Löffler, M. Kapoor, S. Kawai, et al. 2009. Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP. Journal of Immunology 183 (2): 1328–1336.CrossRefGoogle Scholar
  21. 21.
    Sheibanie, A.F., I. Tadmori, H. Jing, E. Vassiliou, and D. Ganea. 2004. Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells. The FASEB Journal 18 (11): 1318–1320.CrossRefPubMedGoogle Scholar
  22. 22.
    Boniface, K., K.S. Bak-Jensen, Y. Li, W.M. Blumenschein, M.J. McGeachy, T.K. McClanahan, et al. 2009. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. The Journal of Experimental Medicine 206 (3): 535–548.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Nishigaki, N., M. Negishi, and A. Ichikawa. 1996. Two Gs-coupled prostaglandin E receptor subtypes, EP2 and EP4, differ in desensitization and sensitivity to the metabolic inactivation of the agonist. Molecular Pharmacology 50 (4): 1031–1037.PubMedGoogle Scholar
  24. 24.
    Yang, X.D., C. Wang, P. Zhou, J. Yu, J. Asenso, Y. Ma, et al. 2016. Absorption characteristic of paeoniflorin-6′-O-benzene sulfonate (CP-25) in in situ singlepass intestinal perfusion in rats. Xenobiotica 46 (9): 775–783.CrossRefPubMedGoogle Scholar
  25. 25.
    Chang, Y., X. Jia, F. Wei, C. Wang, X. Sun, S. Xu, et al. 2016. CP-25, a novel compound, protects against autoimmune arthritis by modulating immune mediators of inflammation and bone damage. Scientific Reports 6: 26239.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jia, X., F. Wei, X. Sun, Y. Chang, S. Xu, X. Yang, et al. 2016. CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured with BAFF-activated CD4(+) T cells. Journal of Ethnopharmacology 189: 194–201.CrossRefPubMedGoogle Scholar
  27. 27.
    Li, Y., K. Sheng, J. Chen, Y. Wu, F. Zhang, Y. Chang, et al. 2015. 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. European Journal of Pharmacology 769: 8–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Abd El-Rahman, R.S., G.M. Suddek, N.M. Gameil, and H.A. El-Kashef. 2011. Protective potential of MMR vaccine against complete Freund's adjuvant-induced inflammation in rats. Inflammopharmacology 19 (6): 343–348.CrossRefPubMedGoogle Scholar
  29. 29.
    Wooley, P.H. 1991. Animal models of rheumatoid arthritis. Current Opinion in Rheumatology 3 (3): 407–420.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang, Z.R., H. Wu, R. Wang, S.P. Li, L. Dai, and W. Wang. 2017. Immune tolerance effect in mesenteric lymph node lymphocytes of geniposide on adjuvant arthritis rats. Phytotherapy Research 31 (8): 1249–1256.CrossRefPubMedGoogle Scholar
  31. 31.
    Chang, Y., X. Sun, X. Jia, S. Xu, F. Wei, X. Yang, et al. 2015. Expression and effects of B-lymphocyte stimulator and its receptors in T cell-mediated autoimmune arthritis. International Immunopharmacology 24 (2): 451–457.CrossRefPubMedGoogle Scholar
  32. 32.
    Lian, X.F., Y.T. Yang, Z.H. Wang, Y. Yang, Y. Yang, Y.W. Shu, et al. 2013. Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activities. Phytotherapy Research 27 (9): 1321–1327.CrossRefPubMedGoogle Scholar
  33. 33.
    Mebius, R.E., and G. Kraal. 2005. Structure and function of the spleen. Nature Reviews. Immunology 5 (8): 606–616.CrossRefPubMedGoogle Scholar
  34. 34.
    McInnes, I.B., and G. Schett. 2011. The pathogenesis of rheumatoid arthritis. The New England Journal of Medicine 365 (23): 2205–2219.CrossRefPubMedGoogle Scholar
  35. 35.
    Liu, Z., B. Li, X. Li, L. Zhang, and L. Lai. 2011. Identification of small-molecule inhibitors against human leukocyte antigen-death receptor 4 (HLA-DR4) through a comprehensive strategy. Journal of Chemical Information and Modeling 51 (2): 326–334.CrossRefPubMedGoogle Scholar
  36. 36.
    Niu, Y., Q. Dong, and R. Li. 2017. Matrine regulates Th1/Th2 cytokine responses in rheumatoid arthritis by attenuating the NF-κB signaling. Cell Biology International 41 (6): 611–621.CrossRefPubMedGoogle Scholar
  37. 37.
    Wu, H., W. Wei, L. Song, L. Zhang, Y. Chen, and X. Hu. 2007. Paeoniflorin induced immune tolerance of mesenteric lymph node lymphocytes via enhancing beta 2-adrenergic receptor desensitization in rats with adjuvant arthritis. International Immunopharmacology 7 (5): 662–673.CrossRefPubMedGoogle Scholar
  38. 38.
    Chen, J.Y., H.X. Wu, J.Y. Chen, L.L. Zhang, Q.T. Wang, W.Y. Sun, et al. 2012. Paeoniflorin inhibits proliferation of fibroblast-like synoviocytes through suppressing G-protein-coupled receptor kinase 2. Planta Medica 78 (7): 665–671.CrossRefPubMedGoogle Scholar
  39. 39.
    Honda, T., E. Segi-Nishida, Y. Miyachi, and S. Narumiva. 2006. Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. The Journal of Experimental Medicine 203 (2): 325–335.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Abrahao, A.C., R.M. Castilho, C.H. Squarize, A.A. Molinolo, D. dos Santos-Pinto Jr., and J.S. Gutkind. 2010. A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation. Oral Oncology 46 (12): 880–887.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Nataraj, C., D.W. Thomas, S.L. Tilley, M.T. Nguyen, R. Mannon, B.H. Koller, et al. 2001. Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. The Journal of Clinical Investigation 108 (8): 1229–1235.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kabashima, K., T. Saji, T. Murata, M. Nagamachi, T. Matsuoka, E. Segi, et al. 2002. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. The Journal of Clinical Investigation 109 (7): 883–893.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Vang, T., K.M. Torgersen, V. Sundvold, M. Saxena, F.O. Levy, B.S. Skålhegg, et al. 2001. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. The Journal of Experimental Medicine 193 (4): 497–507.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Vang, T., H. Abrahamsen, S. Myklebust, V. Horejsí, and K. Taskén. 2003. Combined spatial and enzymatic regulation of Csk by cAMP and protein kinase a inhibits T cell receptor signaling. The Journal of Biological Chemistry 278 (20): 17597–17600.CrossRefPubMedGoogle Scholar
  45. 45.
    Bush, K.A., K.M. Farmer, J.S. Walker, and B.W. Kirkham. 2002. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis and Rheumatism 46 (3): 802–805.CrossRefPubMedGoogle Scholar
  46. 46.
    Nishigaki, N., M. Negishi, A. Honda, Y. Sugimoto, T. Namba, S. Narumiya, et al. 1995. Identification of prostaglandin E receptor ‘EP2’ cloned from mastocytoma cells EP4 subtype. FEBS Letters 1364 (3): 339–341.CrossRefGoogle Scholar
  47. 47.
    Jia, X.Y., Y. Chang, X.J. Sun, X. Dai, and W. Wei. 2014. The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis. International Immunopharmacology 23 (1): 163–169.CrossRefPubMedGoogle Scholar
  48. 48.
    Kojima, F., H. Naraba, Y. Sasaki, M. Beppu, H. Aoki, and S. Kawai. 2003. Prostaglandin E2 is an enhancer of interleukin-1beta-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts. Arthritis and Rheumatism 48 (10): 2819–2828.CrossRefPubMedGoogle Scholar
  49. 49.
    Li, Y., Y. Shen, P. Hohensinner, J. Ju, Z. Wen, S.B. Goodman, et al. 2016. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45 (4): 903–916.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang, C.J., F. Heuts, V. Ovcinnikovs, L. Wardzinski, C. Bowers, E.M. Schmidt, et al. 2015. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proceedings of the National Academy of Sciences of the United States of America 112 (2): 524–529.CrossRefPubMedGoogle Scholar
  51. 51.
    Azuma, M., D. Ito, H. Yagita, K. Okumura, J.H. Phillips, L.L. Lanier, et al. 1993. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 66 (6450): 76–79.CrossRefGoogle Scholar
  52. 52.
    Slavik, J.M., J.E. Hutchcroft, and B.E. Bierer. 1999. CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28. The Journal of Biological Chemistry 274 (5): 3116–3124.CrossRefPubMedGoogle Scholar
  53. 53.
    Zhang, L.L., W. Wei, N.P. Wang, Q.T. Wang, J.Y. Chen, Y. Chen, et al. 2008. Paeoniflorin suppresses inflammatory mediator production and regulates G protein-coupled signaling in fibroblast-like synoviocytes of collagen induced arthritic rats. Inflammation Research 57 (8): 388–395.CrossRefPubMedGoogle Scholar
  54. 54.
    Wang, Q., L. Wang, L. Wu, M. Zhang, S. Hu, R. Wang, et al. 2017. Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis. Scientific Reports 7: 45364.CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune MedicineMinistry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune MedicineHefeiChina

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