Abstract
Extracts of Tripterygium wilfordii hook. f. (leigong teng, Thundergod vine) are effective in traditional Chinese medicine for treatment of immune inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus, nephritis and asthma. Characterisation of the terpenoids present in extracts of Tripterygium identified triptolide, a diterpenoid triepoxide, as responsible for most of the immunosuppressive, anti-inflammatory and antiproliferative effects observed in vitro. Triptolide inhibits lymphocyte activation and T-cell expression of interleukin-2 at the level of transcription. In all cell types examined, triptolide inhibits nuclear factor-κB transcriptional activation at a unique step in the nucleus after binding to DNA. Further characterisation of the molecular mechanisms of triptolide action will serve to elucidate pathways of immune system regulation.
Similar content being viewed by others
References
Tao X, Lipsky PE. The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Rheum Dis Clin North Am 2000; 26 (1): 29–50, viii
Zheng JR, Liu JH, Hsu LF, et al. Toxicity of total glycosides in Tripterygium wilfordii [in Chinese]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 1983; 5 (2): 73–8
Qian SZ. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation. Contraception 1987; 36 (3): 335–45
Chou WC, Wu CC, Yang PC, et al. Hypovolemic shock and mortality after ingestion of Tripterygium wilfordii hook F: a case report. Int J Cardiol 1995; 49 (2): 173–7
Chen K, Shi QA, Fujioka T, et al. Anti-AIDS agents, 4. Tripterifordin, a novel anti-HIV principle from Tripterygium wilfordii: isolation and structural elucidation. J Nat Prod 1992; 55 (1): 88–92
Duan H, Takaishi Y, Imakura Y, et al. Sesquiterpene alkaloids from Tripterygium hypoglaucum and Tripterygium wilfordii: a new class of potent anti-HIV agents. J Nat Prod 2000; 63 (3): 357–61
Tao X, Cai JJ, Lipsky PE. The identity of immunosuppressive components of the ethyl acetate extract and chloroform methanol extract (T2) of Tripterygium wilfordii Hook. F. J Pharmacol Exp Ther 1995; 272 (3): 1305–12
Tao X, Cush JJ, Garret M, et al. A phase I study of ethyl acetate extract of the Chinese antirheumatic herb Tripterygium wilfordii hook F in rheumatoid arthritis. J Rheumatol 2001; 28 (10): 2160–7
Sher FT, Berchtold GA. Studies on the total synthesis of triptolide. I. J Org Chem 1977; 42 (15): 2569–74
Yang D, Ye XY, Xu M. Enantioselective total synthesis of (−)- triptolide, (−)-triptonide, (+)-triptophenolide, and (+)- triptoquinonide. J Org Chem 2000; 65 (7): 2208–17
Tao XL, Sun Y, Dong Y, et al. A prospective, controlled, double-blind, cross-over study of Tripterygium wilfordii hook F in treatment of rheumatoid arthritis. Chin Med J (Engl) 1989; 102 (5): 327–32
Wang J, Xu R, Jin R, et al. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii: I. prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine. Transplantation 2000; 70 (3): 447–55
Faul JL, Nishimura T, Berry GJ, et al. Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2000; 162 (6): 2252–8
Hachida M, Lu H, Zhang X, et al. Inhibitory effect of triptolide on platelet derived growth factor-A and coronary arteriosclerosis after heart transplantation. Transplant Proc 1999; 31 (7): 2719–23
Ren B, Sun J, Hu C, et al. Immunosuppressive effects of Tripterygium wilfordii hook F in a rat liver transplant model. Transplant Proc 2001; 33 (1–2): 520–1
Chen BJ, Liu C, Cui X, et al. Prevention of graft vs host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion. Transplantation 2000; 70 (10): 1442–7
Krishna G, Liu K, Shigemitsu H, et al. PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Am J Pathol 2001; 158 (3): 997–1004
Chen BJ, Chen Y, Cui X, et al. Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model. Transplantation 2002; 73 (1): 115–21
Xia S. Organ transplantation. Chin Med J (Engl) 1996; 109 (1): 29–31
Zhang XY, Tsuchiya N, Dohi M, et al. Prolonged survival of MRL-lpr/lpr mice treated with Tripterygium wilfordii Hook- F. Clin Immunol Immunopathol 1992; 62 (1 Pt 1): 66–71
Lei W, Liu L, Xue M. Effect of Tripterygium wolfordii on inhibition of rejection reaction of allogeneic skin graft in mice [in Chinese]. Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi 1995; 11 (4): 294–5
Li CG. Histopathologic observation on the therapeutic effect of Tripterygium wilfordii in treating experimental allergic encephalomyelitis [in Chinese]. Zhong Xi Yi Jie He Za Zhi 1989; 9 (2): 98–9, 70
Li Z, Li C. Effect of the multiglycoside of Tripterygium wilfordii Hook f. (Tii) on cornea allograft rejection model in rabbit. Yan Ke Xue Bao 1995; 11 (3): 168–72
Liao CX, Li JS. Low-dose cyclosporin A and Tripterygium wilfordii inhibited porcine intestinal allograft rejection. Chin Med J (Engl) 1994; 107 (9): 669–72
Zhou ZS. Rejection and Tripterygium wilfordii-treated small bowel allografts in pigs: pathological studies. Zhonghua Yi Xue Za Zhi 1993; 73 (9): 541–3, 575
Li LS. Clinical and experimental studies on the effect of Tripterygium wilfordii Hook in the treatment of nephritis. Zhonghua Yi Xue Za Zhi 1982; 62 (10): 581–5
Asano K, Yu Y, Kasahara T, et al. Inhibition of murine chronic graft-versus-host disease by the chloroform extract of Tripterygium wilfordii Hook f. Transpl Immunol 1997; 5 (4): 315–9
Asano K, Matsuishi J, Yu Y, et al. Suppressive effects of Tripterygium wilfordii Hook f., a traditional Chinese medicine, on collagen arthritis in mice. Immunopharmacology 1998; 39 (2): 117–26
Gu WZ, Banerjee S, Rauch J, et al. Suppression of renal disease and arthritis, and prolongation of survival in MRL-lpr mice treated with an extract of Tripterygium wilfordii Hook f. Arthritis Rheum 1992; 35 (11): 1381–6
Zhao B, Huang XC, Du HW. Tripterygium wilfordii on prolonging the survival time of myocardial allografts in mice [in Chinese]. Zhong Xi Yi Jie He Za Zhi 1988; 8 (1): 31–3, 6
Wang J, Xu R, Jin R, et al. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii: II. Prolongation of hamster-to-rat cardiac xenograft survival by combination therapy with the PG27 extract and cyclosporine. Transplantation 2000; 70 (3): 456–64
Hachida M, Zhang XL, Lu H, et al. Late multiglycosidorum tripterygium treatment ameliorates established graft coronary arteriosclerosis after heart transplantation in the rat. Transplant Proc 1999; 31 (5): 2020–4
Goker H, Haznedaroglu IC, Chao NJ. Acute graft vs host disease: pathobiology and management. Exp Hematol 2001; 29 (3): 259–77
Chen Y, Zeng D, Schlegel PG, et al. PG27, an extract of Tripterygium wilfordii hook f, induces antigen-specific tolerance in bone marrow transplantation in mice. Blood 2000; 95 (2): 705–10
Fishman AP. Etiology and pathogenesis of primary pulmonary hypertension: a perspective. Chest 1998; 114 (3 Suppl.): 242S–7S
Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension: a morphometric and immunohistochemical study. Am J Respir Crit Care Med 2000; 162 (4 Pt 1): 1577–86
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334 (5): 296–302
Tanaka Y, Schuster DP, Davis EC, et al. The role of vascular injury and hemodynamics in rat pulmonary artery remodeling. J Clin Invest 1996; 98 (2): 434–42
Nishimura T, Faul JL, Berry GJ, et al. 40-O- (2-Hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2001; 163 (2): 498–502
Pan LC, Wilson DW, Segall HJ. Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease. Toxicology 1993; 79 (1): 21–35
Lame MW, Jones AD, Wilson DW, et al. Protein targets of monocrotaline pyrrole in pulmonary artery endothelial cells. J Biol Chem 2000; 275 (37): 29091–9
Ushiro S, Ono M, Nakayama J, et al. New nortriterpenoid isolated from anti-rheumatoid arthritic plant, Tripterygium wilfordii, modulates tumor growth and neovascularization. Int J Cancer 1997; 72 (4): 657–63
Kupchan SM, Court WA, Dailey Jr R, et al. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. J Am Chem Soc 1972; 94 (20): 7194–5
Wei YS, Adachi I. Inhibitory effect of triptolide on colony formation of breast and stomach cancer cell lines. Chung Kuo Yao Li Hsueh Pao 1991; 12 (5): 406–10
Shamon LA, Pezzuto JM, Graves JM, et al. Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii. Cancer Lett 1997; 112 (1): 113–7
Kupchan SM, Schubert RM. Selective alkylation: a biomimetic reaction of the antileukemic triptolides? Science 1974; 185 (153): 791–3
Qiu D, Zhao G, Aoki Y, et al. Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T- cells and NFkappaB transcriptional activation. J Biol Chem 1999; 274 (19): 13443–50
Tao X, Davis LS, Lipsky PE. Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii hook F on human immune responsiveness. Arthritis Rheum 1991; 34 (10): 1274–81
Tao X, Schulze-Koops H, Ma L, et al. Effects of Tripterygium wilfordii Hook f extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production. Arthritis Rheum 1998; 41 (1): 130–8
Yang SX, Gao HL, Xie SS, et al. Immunosuppression of triptolide and its effect on skin allograft survival. Int J Immunopharmacol 1992; 14 (6): 963–9
Zhao G, Vaszar LT, Qiu D, et al. Antiinflammatory effects of triptolide in human bronchial epithelial cells. Am J Physiol 2000; 279: L958–66
Chan MA, Kohlmeier JE, Branden M, et al. Triptolide is more effective in preventing T cell proliferation and interferongamma production than is FK506. Phytother Res 1999; 13 (6): 464–7
Lin N, Sato T, Ito A. Triptolide, a novel diterpenoid triepoxide from Tripterygium wilfordii Hook. f., suppresses the production and gene expression of pro-matrix metalloproteinases 1 and 3 and augments those of tissue inhibitors of metalloproteinases 1 and 2 in human synovial fibroblasts. Arthritis Rheum 2001; 44 (9): 2193–200
Hu KB, Liu ZH, Guo XH, et al. Triptolide inhibits vascular endothelial growth factor expression and production in endothelial cells. Acta Pharmacol Sin 2001; 22 7): 651–6
Yang SX, Xie SS, Gao HL, et al. Triptolide suppresses T-lymphocyte proliferation by inhibiting interleukin-2 receptor expression, but spares interleukin-2 production and mRNA expression. Int J Immunopharmacol 1994; 16 (11): 895–904
Tao X, Davis LS, Hashimoto K, et al. The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. J Pharmacol Exp Ther 1996; 276 (1): 316–25
Chang WT, Kang JJ, Lee KY, et al. Triptolide and chemotherapy cooperate in tumor cell apoptosis: a role for the p53 pathway. J Biol Chem 2001; 276 (3): 2221–7
Jiang XH, Wong BC, Lin MC, et al. Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene 2001; 20 (55): 8009–18
Maekawa K, Yoshikawa N, Du J, et al. The molecular mechanism of inhibition of interleukin-1beta-induced cyclooxygenase-2 expression in human synovial cells by Tripterygium wilfordii Hook F extract. Inflamm Res 1999; 48 (11): 575–81
Chang DM, Kuo SY, Lai JH, et al. Effects of anti-rheumatic herbal medicines on cellular adhesion molecules. Ann Rheum Dis 1999; 58 (6): 366–71
Matlin SA, Belenguer A, Stacey VE, et al. Male antifertility compounds from Tripterygium wilfordii Hook f. Contraception 1993; 47 (4): 387–400
Zhen QS, Ye X, Wei ZJ. Recent progress in research on Tripterygium: a male antifertility plant. Contraception 1995; 51 (2): 121–9
Lee KY, Chang W, Qiu D, et al. PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells. J Biol Chem 1999; 274 (19): 13451–5
National Cancer Institute. Developmental therapeutics program [online]. Available from: http://dtp.nci.nih.gov/docs/dtp_search.html [Accessed 2002 Dec 09]
Yang Y, Liu Z, Tolosa E, et al. Triptolide induces apoptotic death of T lymphocyte. Immunopharmacology 1998; 40 (2): 139–49
Chan EW, Cheng SC, Sin FW, et al. Triptolide induced cytotoxic effects on human promyelocytic leukemia, T cell lymphoma and human hepatocellular carcinoma cell lines. Toxicol Lett 2001; 122 (1): 81–7
Kiviharju TM, Lecane PS, Sellers RG, et al. Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res 2002; 8 (8): 2666–74
Cantrell D. T cell antigen receptor signal transduction pathways. Annu Rev Immunol 1996; 14: 259–74
Adcock IM. Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. Monaldi Arch Chest Dis 1997; 52 (2): 178–86
Pu LX, Zhang TM. Effects of triptolide on T lymphocyte functions in mice. Chung Kuo Yao Li Hsueh Pao 1990; 11 (1): 76–9
Serfling E, Avots A, Neumann M. The architecture of the interleukin-2 promoter: a reflection of T-lymphocyte activation. Biochim Biophys Acta 1995; 1263: 181–200
Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997; 15: 707–47
Emmel EA, Verweij CL, Durand DB, et al. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 1989; 246: 1617–20
Mouzaki A, Dai Y, Weil R, et al. Cyclosporin A and FK506 prevent the derepression of the IL-2 gene in mitogen-induced primary T lymphocytes. Cytokine 1992; 4: 151–60
Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Soc Nephrol 1999; 10 (6): 1366–80
Los M, Schenk H, Hexel K, et al. IL-2 gene expression and NF-kB activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO Journal 1995; 14: 3731–40
Durand DB, Shaw JP, Bush MR, et al. Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol 1988; 8 (4): 1715–24
Garrity PA, Chen D, Rothenberg EV, et al. Interleukin-2 transcription is regulated in vivo at the level of coordinated binding of both constitutive and regulated factors. Mol Cell Biol 1994; 14 (3): 2159–69
Ward SB, Hernandez-Hoyos G, Chen F, et al. Chromatin remodeling of the interleukin-2 gene: distinct alterations in the proximal versus distal enhancer regions. Nucleic Acids Res 1998; 26 (12): 2923–34
Northrop JP, Ullman KS, Crabtree GR. Characterization of the nuclear and cytoplasmic components of the lymphoidspecific nuclear factor of activated T cells (NFAT) complex. J Biol Chem 1993; 268: 2917–23
Crabtree GR. Calcium, calcineurin, and the control of transcription. J Biol Chem 2001; 276 (4): 2313–6
Xanthoudakis S, Viola JP, Shaw KT, et al. An enhanced immune response in mice lacking the transcription factor NFAT1. Science 1996; 272: 892–5
de la Pompa JL, Timmerman LA, Takimoto H, et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 1998; 392 (6672): 182–6
Kao PN, Chen L, Brock G, et al. Cloning and expression of cyclosporin A- and FK506-sensitive nuclear factor of activated T-cells: NF45 and NF90. J Biol Chem 1994; 269 (32): 20691–9
Aoki Y, Zhao G, Qiu D, et al. CsA-sensitive purine-box transcriptional regulator in bronchial epithelial cells contains NF45, NF90, and Ku. Am J Physiol 1998; 275 (6 Pt 1): L1164–72
Ting NSY, Kao PN, Chan DW, et al. DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45. J Biol Chem 1998; 273: 2136–45
Gu Y, Seidl KJ, Rathbun GA, et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 1997; 7 (5): 653–65
Ouyang H, Nussenzweig A, Kurimasa A, et al. Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J Exp Med 1997; 186 (6): 921–9
Nussenzweig A, Chen C, da Costa Soares V, et al. Requirement for Ku80 in growth and immunoglobulin V (D)J recombination. Nature 1996; 382 (6591): 551–5
Zhu C, Bogue MA, Lim DS, et al. Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V (D)J recombination intermediates. Cell 1996; 86 (3): 379–89
Gao Y, Chaudhuri J, Zhu C, et al. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V (D)J recombination. Immunity 1998; 9 (3): 367–76
Taccioli GE, Amatucci AG, Beamish HJ, et al. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 1998; 9 (3): 355–66
Kurimasa A, Ouyang H, Dong LJ, et al. Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. Proc Natl Acad Sci US A 1999; 96 (4): 1403–8
Liu J, Farmer Jr J, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP- FK506 complexes. Cell 1991; 66 (4): 807–15
Baldwin Jr A. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649–83
Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336 (15): 1066–71
Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell 1998; 1 (5): 661–71
Zhong H, May MJ, Jimi E, et al. The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol Cell 2002; 9 (3): 625–36
Ashburner BP, Westerheide SD, Baldwin Jr AS. The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol 2001; 21 (20): 7065–77
Aoki Y, Qiu D, Zhao GH, et al. Leukotriene B4 mediates histamine induction of NF-kB and IL-8 in human bronchial epithelial cells. Am J Physiol 1998; 274: L1030–9
Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996; 274 (5288): 782–4
Zong WX, Edelstein LC, Chen C, et al. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev 1999; 13 (4): 382–7
Acknowledgements
Dr Kao has received consultant fees from Pharmagenesis (Palo Alto, CA, USA). The research findings described have been supported by NIH grants AI39624 and HL62588, and by industrial grants from Pharmagenesis to PNK.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Qiu, D., Kao, P.N. Immunosuppressive and Anti-Inflammatory Mechanisms of Triptolide, the Principal Active Diterpenoid from the Chinese Medicinal Herb Tripterygium wilfordii Hook. f.. Drugs in R&D 4, 1–18 (2003). https://doi.org/10.2165/00126839-200304010-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00126839-200304010-00001