Planta Med 2010; 76(13): 1424-1430
DOI: 10.1055/s-0029-1240909
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Tetrandrine Attenuates Dendritic Cell-mediated Alloimmune Responses and Prolongs Graft Survival in Mice

Yun Chen1 , 2 , 3 , Hong-Shiee Lai2 [*] , Bor-Luen Chiang4 , 5 , 6 , Sheng-Hong Tseng2 [*] , Wei-Jao Chen2
  • 1Department of Surgery, Far Eastern Memorial Hospital, Taipei, Taiwan
  • 2Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
  • 3Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan
  • 4Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
  • 5Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  • 6Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
Further Information

Publication History

received August 14, 2009 revised January 23, 2010

accepted January 27, 2010

Publication Date:
25 February 2010 (online)

Abstract

Tetrandrine, a bisbenzylisoquinoline alkaloid, has significant immunosuppressive effects; however, the effects of tetrandrine on dendritic cells (DCs) and the associated immune reactions are unclear. In this study, we investigated the effects of tetrandrine on DCs and the effects of the tetrandrine-treated DCs on alloimmune reactions in vitro and graft survival in vivo. Tetrandrine significantly downregulated the expression of CD80 and CD86 of DCs and increased their secretion of IL-10 (p = 0.0001). Mixed leukocyte reaction showed that tetrandrine inhibited dendritic-cell allo-stimulatory activity, which was reversed by the anti-IL-10 treatment. An in vivo study demonstrated that tetrandrine-treated DCs prolonged the survival time of skin grafts in mice compared to control (p = 0.005) and decreased cellular infiltration of the graft in the histopathological study. The data suggest that tetrandrine-treated DCs cause immunosuppression and protect skin grafts from rejection. The tetrandrine-induced immunosuppression seems to be partially due to increased IL-10 secretion.

References

  • 1 Wang G, Lemos J R, Iadecola C. Herbal alkaloid tetrandrine: from an ion channel blocker to inhibitor of tumor proliferation.  Trends Pharmacol Sci. 2004;  25 120-123
  • 2 Chen Y, Chen J C, Tseng S H. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats.  Int J Cancer. 2009;  124 2260-2269
  • 3 Chen Y, Chen J C, Tseng S H. Effects of tetrandrine plus radiation on neuroblastoma cells.  Anticancer Res. 2009;  29 3163-3171
  • 4 Lee S H, Nan J X, Sohn D H. Tetrandrine prevents tissue inhibitor of metalloproteinase-1 messenger RNA expression in rat liver fibrosis.  Pharmacol Toxicol. 2001;  89 214-216
  • 5 Xiao J G, Wu S Y, Wang Y L, Li J G, Zhang S P. Inhibitory effects of tetrandrine on bovine serum albumin-induced uveitis in rabbits.  J Ocular Pharmacol. 1993;  9 151-156
  • 6 Wu J M, Chen Y, Chen J C, Lin T Y, Tseng S H. Tetrandrine induces apoptosis and growth suppression of colon cancer cells in mice.  Cancer Lett. 2010;  287 187-195
  • 7 Lin T Z, Tseng S H, Li S J, Chen J C, Shieh J S, Chen Y. Tetrandrine increased the survival rate of mice with lipopolysaccharide-induced endotoxemia.  J Trauma. 2009;  66 411-417
  • 8 Chen Y, Wu J M, Lin T Z, Wu C C, Chiu K M, Chang B F, Tseng S H, Chu S H. Tetrandrine ameliorated reperfusion injury of small bowel transplantation.  J Ped Surg. 2009;  44 2145-2152
  • 9 Ferrante A, Seow W K, Rowan-Kelly B, Thong Y H. Tetrandrine, a plant alkaloid, inhibits production of tumour necrosis factor-alpha (cachectin) by human monocytes.  Clin Exp Immunol. 1990;  80 232-235
  • 10 Chang D M, Chang W Y, Kuo S Y, Chang M L. The effects of traditional antirheumatic herbal medicines on immune response cells.  J Rheumatol. 1997;  24 436-441
  • 11 Kondo Y, Takano F, Hojo H. Inhibitory effect of bis-benzylisoquinoline alkaloids on nitric oxide production in activated macrophages.  Biochem Pharmacol. 1993;  46 1887-1892
  • 12 Lai J H, Ho L J, Lu K C, Chang D M, Shaio M F, Han S H. Western and Chinese antirheumatic drug-induced T cell apoptotic DNA damage uses different caspase cascades and is independent of Fas/Fas ligand interaction.  J Immunol. 2001;  166 6914-6924
  • 13 Wells A D, Li X C, Li Y, Walsh M C, Zheng X X, Wu Z, Nuñez G, Tang A, Sayegh M, Hancock W W, Strom T B, Turka L A. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.  Nat Med. 1999;  5 1303-1307
  • 14 Fairchild P, Waldmann H. Dendritic cells and prospects for transplantation tolerance.  Curr Opin Immunol. 2000;  12 528-535
  • 15 Fu F, Li Y, Qian S, Lu L, Chambers F, Starzl T E, Fung J J, Thomson A W. Costimulatory molecule-deficient dendritic cell progenitors (MHC class II +, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipient.  Transplantation. 1996;  62 659-665
  • 16 Lu L, Thomson A W. Manipulation of dendritic cells for tolerance induction in transplantation and autoimmune disease.  Transplantation. 2002;  73 (Suppl. 1) S19-S22
  • 17 Thomson A W, Lu L. Dendritic cells as regulators of immune reactivity: implications for transplantation.  Transplantation. 1999;  68 1-8
  • 18 Thomson A W, Turnquist H R, Zahorchak A F, Raimondi G. Tolerongenic dendritic cell-regulatory T-cell interaction and the promotion of transplant tolerance.  Transplantation. 2009;  87 (Suppl. 9) S86-S90
  • 19 Xu M Q, Suo Y P, Gong J P, Zhang M M, Yan L N. Prolongation of liver allograft survival by dendritic cells modified with NF-kappaB decoy oligonucleotides.  World J Gastroenterol. 2004;  10 2361-2368
  • 20 Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman R M. Generation of large numbers of dendritic cells from a mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.  J Exp Med. 1992;  176 1693-1702
  • 21 Billingham R E, Medawar P B. The technique of free skin grafting in mammals.  Br J Exp Biol. 1952;  26 385-402
  • 22 Zhang Z X, Yang L, Young K J, DuTemple B, Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression.  Nat Med. 2000;  6 782-789
  • 23 Bell B, Young J W, Banchereau J. Dendritic cells.  Adv Immunol. 1999;  72 255-324
  • 24 Griffin M D, Lutz W, Phan V A, Bachman L A, McKean D J, Kumar R. Dendritic cell modulation by 1α,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo.  Proc Natl Acad Sci USA. 2001;  98 6800-6805
  • 25 Lutz M B, Suri R M, Niimi M, Ogilvie A L, Kukutsch N A, Rössner S, Schuler G, Austyn J M. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo.  Eur J Immunol. 2000;  30 1813-1822
  • 26 Lai J H, Ho L J, Kwan C Y, Chang D M, Lee T C. Plant alkaloid tetrandrine and its analog block CD28-costimulated activities of human peripheral blood T cells.  Transplantation. 1999;  68 1383-1392
  • 27 Nickerson P, Steurer W, Steiger J, Zheng X, Steele A W, Strom T B. Cytokines and the Th1/Th2 paradigm in transplantation.  Curr Opin Immunol. 1994;  6 757-764
  • 28 Kalinski P, Hilkens C M, Wierenga E A, Kapsenberg M L. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal.  Immunol Today. 1999;  20 561-567
  • 29 Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk A H. Induction of tolerance by IL-10-treated dendritic cells.  J Immunol. 1997;  159 4772-4780
  • 30 Li S Y, Teh B S, Seow W K, Ling L H, Thong Y H. Effect of tetrandrine on immunological response and cardiac transplant rejection in mice.  Int Arch Allergy Appl Immunol. 1989;  90 169-173

1 Both authors contributed equally to this work.

Dr. Sheng-Hong Tseng

Department of Surgery
National Taiwan University Hospital and National Taiwan University College of Medicine

7 Chung-Shan S. Rd.

Taipei 100

Taiwan

Phone: + 88 62 23 12 34 56, ext. 6 51 10

Fax: + 88 62 89 66 55 67

Email: tsh5110@ntu.edu.tw

    >