Advertisement

Journal of Clinical Immunology

, Volume 27, Issue 1, pp 36–45 | Cite as

Rosmarinic Acid Induces Apoptosis of Activated T Cells from Rheumatoid Arthritis Patients via Mitochondrial Pathway

  • YUN-GYOUNG HUR
  • CHANG-HEE SUH
  • SUNGJOO KIM
  • JONGHWA WONEmail author
Article

T cells play an important role in the initiation and the progression of rheumatoid arthritis (RA) and depletion of potentially pathogenic T cells was suggested as an important therapeutic protocol. We determined if rosmarinic acid (RosA), known as a secondary metabolite from herbal plants, had apoptotic activity toward T cells from RA patients and further verified target T-cell subsets. CD3+CD25+ activated T-cell subsets from most of the RA patients displayed significantly higher apoptosis rates than did the PBMCs and total CD3+ T cells. Furthermore, activated and effector CD4+ T cells, including CD4+CD25+ and CD4+CD45RO+ T cells, had a tendency of being more susceptible to RosA-induced apoptosis than that of resting and naïve T-cell subsets. RosA induced the release of cytochrome c from mitochondria and the blockage of mitochondrial depolarization inhibited apoptosis. Taken together, these results suggest that RosA induces apoptosis of activated T-cell subsets from RA patients via a mitochondrial pathway.

KEY WORDS

T cell rheumatoid arthritis rosmarinic acid apoptosis 

Abbreviations used:

RA

rheumatoid arthritis

RosA

rosmarinic acid

CII

type II collagen

RANKL

receptor activator of NF-κB ligand

FasL

Fas ligand

MMP

mitochondrial membrane potential

BA

bongkrekic acid.

Notes

ACKNOWLEDGMENTS

This work was supported by the Green Cross Corp. and by the Korean Ministry of Science and Technology under Grant CBM2-A500-001-1-0-0.

REFERENCES

  1. 1.
    Firestein GS: Evolving concepts of rheumatoid arthritis. Nature 423:356–361, 2003PubMedCrossRefGoogle Scholar
  2. 2.
    VanderBorght A, Geusens P, Raus J, Stinissen P: The autoimmune pathogenesis of rheumatoid arthritis: Role of autoreactive T cells and new immunotherapies. Semin Arthritis Rheum 31:160–175, 2001PubMedCrossRefGoogle Scholar
  3. 3.
    Granholm NA, Cavallo T: Autoimmunity, polyclonal B-cell activation and infection. Lupus 1:63–74, 1992PubMedGoogle Scholar
  4. 4.
    Nepom GT, Byers P, Seyfried C, Healey LA, Wilske KR, Stage D, Nepom BS: HLA genes associated with rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes. Arthritis Rheum 32:15–21, 1989PubMedGoogle Scholar
  5. 5.
    Gumanovskaya ML, Myers LK, Rosloniec EF, Stuart JM, Kang AH: Intravenous tolerization with type II collagen induces interleukin-4-and interleukin-10-producing CD4+ T cells. Immunology 97:466–473, 1999PubMedCrossRefGoogle Scholar
  6. 6.
    Kadowaki KM, Matsuno H, Tsuji H, Tunru I: CD4+ T cells from collagen-induced arthritic mice are essential to transfer arthritis into severe combined immunodeficient mice. Clin Exp Immunol 97:212–218, 1994PubMedCrossRefGoogle Scholar
  7. 7.
    Spargo LD, Cleland LG, Wing SJ, Hawkes JS, Mayrhofer G: Characterization of thoracic duct cells that transfer polyarthritis. Clin Exp Immunol 126:560–569, 2001PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang HG, Yang P, Xie J, Liu Z, Liu D, Xiu L, Zhou T, Wang Y, Hsu HC, Mountz JD: Depletion of collagen II-reactive T cells and blocking of B cell activation prevents collagen II-induced arthritis in DBA/1j mice. J Immunol 168:4164–4172, 2002PubMedGoogle Scholar
  9. 9.
    Tada Y, Nagasawa K, Ho A, Morito F, Ushiyama O, Suzuki N, Ohta H, Mak TW: CD28-deficient mice are highly resistant to collagen-induced arthritis. J Immunol 162:203–208, 1999PubMedGoogle Scholar
  10. 10.
    Nakashima T, Wada T, Penninger JM: RANKL and RANK as novel therapeutic targets for arthritis. Curr Opin Rheumatol 15:280–287, 2003PubMedCrossRefGoogle Scholar
  11. 11.
    Cho ML, Yoon CH, Hwang SY, Park MK, Min SY, Lee SH, Park SH, Kim HY: Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients: Cross-talk between T cells and synovial fibroblasts. Arthritis Rheum 50:776–784, 2004PubMedCrossRefGoogle Scholar
  12. 12.
    Xu G, Nie H, Li N, Zheng W, Zhang D, Feng G, Ni L, Xu R, Hong J, Zhang JZ: Role of osteopontin in amplification and perpetuation of rheumatoid synovitis. J Clin Invest 115:1060–1067, 2005PubMedCrossRefGoogle Scholar
  13. 13.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309, 1999PubMedCrossRefGoogle Scholar
  14. 14.
    Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P: Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970, 1999PubMedCrossRefGoogle Scholar
  15. 15.
    Lubberts E, Van Den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, Joosten LA, Van Den Berg WB: IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol 170:2655–2662, 2003PubMedGoogle Scholar
  16. 16.
    Nakae S, Nambu A, Sudo K, Iwakura Y: Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177, 2003PubMedGoogle Scholar
  17. 17.
    Lubberts E, Koenders MI, Oppers-Walgreen B, Van Den Bersselaar L, Coenen-de Roo CJ, Joosten LA, Van Den Berg WB: Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 50:650–659, 2004PubMedCrossRefGoogle Scholar
  18. 18.
    Ogawa Y, Ohtsuki M, Uzuki M, Sawai T, Onozawa Y, Nakayama J, Yonemura A, Kimura T, Matsuno H: Suppression of osteoclastogenesis in rheumatoid arthritis by induction of apoptosis in activated CD4+ T cells. Arthritis Rheum 48:3350–3358, 2003PubMedCrossRefGoogle Scholar
  19. 19.
    Al-Sereiti MR, Abu-Amer KM, Sen P: Pharmacology of rosmary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian J Exp Biol 37:124–130, 1999PubMedGoogle Scholar
  20. 20.
    Kelm MA, Nair MG, Strasburg GM, DeWitt DL: Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine 7:7–13, 2000PubMedGoogle Scholar
  21. 21.
    Choy EH, Kingsley GH, Panayi GS: Monoclonal antibody therapy in rheumatoid arthritis. Br J Rheumatol 37:484–490, 1998PubMedCrossRefGoogle Scholar
  22. 22.
    Hur YG, Yun Y, Won J: Rosmarinic acid induces p56lck-dependent apoptosis in Jurkat and peripheral T cells via mitochondrial pathway independent from Fas/Fas ligand interaction. J Immunol 172:79–87, 2004PubMedGoogle Scholar
  23. 23.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324, 1998Google Scholar
  24. 24.
    Acuto O, Michel F: CD28-mediated co-stimulation: A quantitative support for TCR signalling. Nat Rev Immunol 3:939–951, 2003PubMedCrossRefGoogle Scholar
  25. 25.
    Schmidt D, Goronzy JJ, Weyand CM: CD4+ CD7− CD28− T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 97:2027–2037, 1996PubMedGoogle Scholar
  26. 26.
    Gerli R, Schillaci G, Giordano A, Bocci EB, Bistoni O, Vaudo G, Marchesi S, Pirro M, Ragni F, Shoenfeld Y, Mannarino E: CD4+CD28− T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation 109:2744–2748, 2004PubMedCrossRefGoogle Scholar
  27. 27.
    Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ: Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28− T cells from rheumatoid arthritis patients. J Immunol 161:1018–1025, 1998PubMedGoogle Scholar
  28. 28.
    Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP: Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349, 1995PubMedCrossRefGoogle Scholar
  29. 29.
    Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969–976, 1994PubMedCrossRefGoogle Scholar
  30. 30.
    Siegel RM, Chan FK, Chun HJ, Lenardo MJ: The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 1:469–474, 2000PubMedCrossRefGoogle Scholar
  31. 31.
    Hoa TT, Hasunuma T, Aono H, Masuko K, Kobata T, Yamamoto K, Sumida T, Nishioka K: Novel mechanisms of selective apoptosis in synovial T cells of patients with rheumatoid arthritis. J Rheumatol 23:1332–1337, 1996PubMedGoogle Scholar
  32. 32.
    Chou CT, Yang JS, Lee MR: Apoptosis in rheumatoid arthritis—Expression of Fas, Fas-L, p53, and Bcl-2 in rheumatoid synovial tissues. J Pathol 193:110–116, 2001PubMedCrossRefGoogle Scholar
  33. 33.
    Salvioli S, Ardizzoni A, Franceschi C, Cossarizza A: JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess delta psi changes in intact cells: Implications for studies on mitochondrial functionality during apoptosis. FEBS Lett 411:77–82, 1997PubMedCrossRefGoogle Scholar
  34. 34.
    Soden M, Hassan J, Scott DL, Hanly JG, Moriarty M, Whelan A, Feighery C, Bresnihan B: Lymphoid irradiation in intractable rheumatoid arthritis. Long-term follow-up of patients treated with 750 rads or 2,000 rads. Arthritis Rheum 32:523–530, 1989PubMedGoogle Scholar
  35. 35.
    Ueki Y, Nakamura H, Kanamoto Y, Miyazaki M, Yano M, Matsumoto K, Miyake S, Tominaga T, Tominaga M, Yamasaki S, Eguchi K: Comparison of lymphocyte depletion and clinical effectiveness on filtration leukocytapheresis in patients with rheumatoid arthritis. Ther Apher 5:455–461, 2001PubMedCrossRefGoogle Scholar
  36. 36.
    Hidaka T, Suzuki K, Matsuki Y, Takamizawa-Matsumoto M, Okada M, Ishizuka T, Kawakami M, Ohsuzu F: Changes in CD4+ T lymphocyte subsets in circulating blood and synovial fluid following filtration leukocytapheresis therapy in patients with rheumatoid arthritis. Ther Apher 3:178–185, 1999PubMedCrossRefGoogle Scholar
  37. 37.
    Herzog C, Walker C, Muller W, Rieber P, Reiter C, Riethmuller G, Wassmer P, Stockinger H, Madic O, Pichler WJ: Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun 2:627–642, 1989PubMedCrossRefGoogle Scholar
  38. 38.
    Kirkham BW, Pitzalis C, Kingsley GH, Chikanza IC, Sabharwal S, Barbatis C, Grahame R, Gibson T, Amlot PL, Panayi GS: Monoclonal antibody treatment in rheumatoid arthritis: The clinical and immunological effects of a CD7 monoclonal antibody. Br J Rheumatol 30:459–463, 1991PubMedCrossRefGoogle Scholar
  39. 39.
    Keystone E: Treatments no longer in development for rheumatoid arthritis. Ann Rheum Dis 61:43–45, 2002Google Scholar
  40. 40.
    Rep MH, van Oosten BW, Roos MT, Ader HJ, Polman CH, van Lier PA: Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans. J Clin Invest 99:2225–2231, 1997PubMedGoogle Scholar
  41. 41.
    Ruderman EM, Weinblatt ME, Thurmond LM, Pinkus GS, Gravallese EM: Synovial tissue response to treatment with Campath-1H. Arthritis Rheum 38:254–258, 1995PubMedGoogle Scholar
  42. 42.
    Liu Z, Xu X, Hsu HC, Tousson A, Yang PA, Wu Q, Liu C, Yu S, Zhang HG, Mountz JD: CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis. J Clin Invest 112:1332–1341, 2003PubMedCrossRefGoogle Scholar
  43. 43.
    Fossiez F, Djossou O, Chomarat P, Flores-Romo L, Ait-Yahia S, Maar C, Pin JJ, Garrone P, Garcia E, Saeland S, Blanchard D, Gaillard C, Das Mahapatra B, Rouvier E, Golstein P, Banchereau J, Lebecque S: T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593–2603, 1996PubMedCrossRefGoogle Scholar
  44. 44.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352, 1999PubMedCrossRefGoogle Scholar
  45. 45.
    Kohem CL, Brezinscheck RI, Wisbey H, Tortorella C, Lipsky PE, Openheimer-Marks N: Enrichment of differentiated CD45Rbdim, CD27-memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 39:844–854, 1996PubMedGoogle Scholar
  46. 46.
    Szodoray P, Jellestad S, Nakken B, Brun JG, Jonsson R: Programmed cell death in rheumatoid arthritis peripheral blood T-cell subpopulations determined by laser scanning cytometry. Lab Invest 83:1839–1848, 2003PubMedCrossRefGoogle Scholar
  47. 47.
    Goronzy JJ, Weyand CM: T-cell regulation in rheumatoid arthritis. Curr Opin Rheumatol 16:212–217, 2004PubMedCrossRefGoogle Scholar
  48. 48.
    Namekawa T, Snyder MR, Yen JH, Goehring BE, Leibson PJ, Weyand CM, Goronzy JJ: Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis. J Immunol 165:1138–1145, 2000PubMedGoogle Scholar
  49. 49.
    Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ: Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28− T cells from rheumatoid arthritis patients. J Immunol 161:1018–1025, 1998PubMedGoogle Scholar
  50. 50.
    Frey O, Petrow PK, Gajda M, Siegmund K, Huehn J, Scheffold A, Hamann A, Radbruch A, Brauer R: The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells. Arthritis Res Ther 7:R291–301, 2005Google Scholar
  51. 51.
    van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS: CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50:2775–2785, 2004PubMedCrossRefGoogle Scholar
  52. 52.
    Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 200:277–285, 2004PubMedCrossRefGoogle Scholar
  53. 53.
    de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager W, Pugayung G, Giannoni F, Rijkers G, Albani S, Kuis W, Prakken B: CD4+CD25 bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435–6443, 2004PubMedGoogle Scholar
  54. 54.
    Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S: Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 105:735–741, 2005PubMedCrossRefGoogle Scholar
  55. 55.
    Goronzy JJ, Weyand CM: Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol 22:251–255, 2001PubMedCrossRefGoogle Scholar
  56. 56.
    Wagner UG, Koetz K, Weyand CM, Goronzy JJ: Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA 95:14447–14452, 1998PubMedCrossRefGoogle Scholar
  57. 57.
    Weyand CM, Goronzy JJ: T-cell responses in rheumatoid arthritis: Systemic abnormalities-local disease. Curr Opin Rheumatol 11:210–217, 1999PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • YUN-GYOUNG HUR
    • 1
  • CHANG-HEE SUH
    • 2
  • SUNGJOO KIM
    • 1
  • JONGHWA WON
    • 1
    • 3
    Email author
  1. 1.Division of Immune RegulationMogam Biotechnology Research InstituteYongin CitySouth Korea
  2. 2.Rheumatology, Arthritis Center, School of MedicineAjou UniversitySuwon CitySouth Korea
  3. 3.Mogam Biotechnology Research InstituteYongin CitySouth Korea

Personalised recommendations