Skip to main content
NCBI home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2003 Jun;12(3):157–166. doi: 10.1080/0962935031000134879

Characterization of the growth-inhibitory and apoptosis-inducing activities of a triterpene saponin, securioside B against BAC1.2F5 macrophages.

Satoru Yui 1, Tomoya Kudo 1, Kazumi Hodono 1, Yoshihiro Mimaki 1, Minpei Kuroda 1, Yutaka Sashida 1, Masatoshi Yamazaki 1
PMCID: PMC1781608  PMID: 12857599

Abstract

BACKGROUND: Since the growth state of macrophages in local pathological sites is considered a factor that regulates the processes of many disease, such as tumors, inflammation, and atherosclerosis, the substances that regulate macrophage growth or survival may be useful for disease control. We previously reported that securiosides A and B, novel triterpene saponins, exerted macrophage-oriented cytotoxicity in the presence of a L-cell-conditioned medium containing macrophage colony-stimulating factor (M-CSF), while the compounds did not exhibit an effect on macrophages in the absence of the growth-stimulating factors. AIM: This study was undertaken to characterize the growth-inhibitory and the apoptosis-inducing activities of securioside B, focusing on the effects of the macrophage-growth factor(s), and to examine the implication of a mitochondria pathway in apoptosis induction. METHODS: The effect of securioside B on a murine macrophage cell line (BAC1.2F5) was examined by MTT assay and lactose dehydrogenase release assay in the presence of L-cell-conditioned medium, M-CSF, or granulocyte-macrophage CSF (GM-CSF). RESULT: Securioside B inhibited the growth of the cells stimulated by recombinant M-CSF or GM-CSF, but it scarcely induced cytolysis of the cells under the same conditions. Moreover, securioside B did not induce cell death when the compound only was added to the cells. On the other hand, the compound extensively induced apoptotic cell death in the presence of L-cell-conditioned medium, suggesting that apoptosis induction by securioside B requires the additional factor(s) present in L-cell-conditioned medium. Securioside B plus L-cell-conditioned medium induced the activation of caspase-3 and caspase-9, but not caspase-8. In addition, cytochrome c release from the mitochondria into the cytosol, and disrupted mitochondria membrane potential, was also observed in the apoptotic BAC1.2F5 cells. CONCLUSION: These data suggest that securioside B has growth-inhibitory activity against growth factor-stimulated macrophages, and that it induces apoptotic macrophage death through the activation of a mitochondrial pathway in the presence of L-cell-conditioned medium.

Full Text

The Full Text of this article is available as a PDF (232.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bitterman P. B., Saltzman L. E., Adelberg S., Ferrans V. J., Crystal R. G. Alveolar macrophage replication. One mechanism for the expansion of the mononuclear phagocyte population in the chronically inflamed lung. J Clin Invest. 1984 Aug;74(2):460–469. doi: 10.1172/JCI111443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
  3. Borges V. M., Falcão H., Leite-Júnior J. H., Alvim L., Teixeira G. P., Russo M., Nóbrega A. F., Lopes M. F., Rocco P. M., Davidson W. F. Fas ligand triggers pulmonary silicosis. J Exp Med. 2001 Jul 16;194(2):155–164. doi: 10.1084/jem.194.2.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen B. D., Clark C. R., Chou T. H. Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor. Blood. 1988 Apr;71(4):997–1002. [PubMed] [Google Scholar]
  5. Chodakewitz J. A., Kupper T. S., Coleman D. L. Keratinocyte-derived granulocyte/macrophage colony-stimulating factor induces DNA synthesis by peritoneal macrophages. J Immunol. 1988 Feb 1;140(3):832–836. [PubMed] [Google Scholar]
  6. De Maria R., Lenti L., Malisan F., d'Agostino F., Tomassini B., Zeuner A., Rippo M. R., Testi R. Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis. Science. 1997 Sep 12;277(5332):1652–1655. doi: 10.1126/science.277.5332.1652. [DOI] [PubMed] [Google Scholar]
  7. Evans R., Cullen R. T. In situ proliferation of intratumor macrophages. J Leukoc Biol. 1984 Jun;35(6):561–572. doi: 10.1002/jlb.35.6.561. [DOI] [PubMed] [Google Scholar]
  8. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gordon D., Reidy M. A., Benditt E. P., Schwartz S. M. Cell proliferation in human coronary arteries. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4600–4604. doi: 10.1073/pnas.87.12.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goto M., Matsuno K., Yamaguchi Y., Ezaki T., Ogawa M. Proliferation kinetics of macrophage subpopulations in a rat experimental pancreatitis model. Arch Histol Cytol. 1993 Mar;56(1):75–82. doi: 10.1679/aohc.56.75. [DOI] [PubMed] [Google Scholar]
  11. Hu Y., Benedict M. A., Ding L., Núez G. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 1999 Jul 1;18(13):3586–3595. doi: 10.1093/emboj/18.13.3586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Joza N., Susin S. A., Daugas E., Stanford W. L., Cho S. K., Li C. Y., Sasaki T., Elia A. J., Cheng H. Y., Ravagnan L. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature. 2001 Mar 29;410(6828):549–554. doi: 10.1038/35069004. [DOI] [PubMed] [Google Scholar]
  13. Kiener P. A., Davis P. M., Starling G. C., Mehlin C., Klebanoff S. J., Ledbetter J. A., Liles W. C. Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages. J Exp Med. 1997 Apr 21;185(8):1511–1516. doi: 10.1084/jem.185.8.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kuroda M., Mimaki Y., Sashida Y., Kitahara M., Yamazaki M., Yui S. Securiosides A and B, novel acylated triterpene bisdesmosides with selective cytotoxic activity against M-CSF-stimulated macrophages. Bioorg Med Chem Lett. 2001 Feb 12;11(3):371–374. doi: 10.1016/s0960-894x(00)00674-0. [DOI] [PubMed] [Google Scholar]
  15. Kurth I., Willimann K., Schaerli P., Hunziker T., Clark-Lewis I., Moser B. Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development. J Exp Med. 2001 Sep 17;194(6):855–861. doi: 10.1084/jem.194.6.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li L. Y., Luo X., Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001 Jul 5;412(6842):95–99. doi: 10.1038/35083620. [DOI] [PubMed] [Google Scholar]
  17. Lin E. Y., Nguyen A. V., Russell R. G., Pollard J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001 Mar 19;193(6):727–740. doi: 10.1084/jem.193.6.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mimaki Yoshihiro, Harada Hiroshi, Sakuma Chiseko, Haraguchi Mitsue, Yui Satoru, Kudo Tomoya, Yamazaki Masatoshi, Sashida Yutaka. Enterolosaponins A and B, novel triterpene bisdesmosides from Enterolobium contortisiliquum, and evaluation for their macrophage-oriented cytotoxic activity. Bioorg Med Chem Lett. 2003 Feb 24;13(4):623–627. doi: 10.1016/s0960-894x(02)01044-2. [DOI] [PubMed] [Google Scholar]
  19. Morgan C., Pollard J. W., Stanley E. R. Isolation and characterization of a cloned growth factor dependent macrophage cell line, BAC1.2F5. J Cell Physiol. 1987 Mar;130(3):420–427. doi: 10.1002/jcp.1041300316. [DOI] [PubMed] [Google Scholar]
  20. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  21. Rosenfeld M. E., Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990 Sep-Oct;10(5):680–687. doi: 10.1161/01.atv.10.5.680. [DOI] [PubMed] [Google Scholar]
  22. Sasaki T., Horiuchi S., Yamazaki M., Yui S. Stimulation of macrophage DNA synthesis by polyanionic substances through binding to the macrophage scavenger receptor. Biol Pharm Bull. 1996 Mar;19(3):449–455. doi: 10.1248/bpb.19.449. [DOI] [PubMed] [Google Scholar]
  23. Stanley E. R., Chen D. M., Lin H. S. Induction of macrophage production and proliferation by a purified colony stimulating factor. Nature. 1978 Jul 13;274(5667):168–170. doi: 10.1038/274168a0. [DOI] [PubMed] [Google Scholar]
  24. Stewart C. C. Local proliferation of mononuclear phagocytes in tumors. J Reticuloendothel Soc. 1983 Jul;34(1):23–27. [PubMed] [Google Scholar]
  25. Strasser A., O'Connor L., Dixit V. M. Apoptosis signaling. Annu Rev Biochem. 2000;69:217–245. doi: 10.1146/annurev.biochem.69.1.217. [DOI] [PubMed] [Google Scholar]
  26. Susin S. A., Zamzami N., Kroemer G. Mitochondria as regulators of apoptosis: doubt no more. Biochim Biophys Acta. 1998 Aug 10;1366(1-2):151–165. doi: 10.1016/s0005-2728(98)00110-8. [DOI] [PubMed] [Google Scholar]
  27. Thornberry N. A., Lazebnik Y. Caspases: enemies within. Science. 1998 Aug 28;281(5381):1312–1316. doi: 10.1126/science.281.5381.1312. [DOI] [PubMed] [Google Scholar]
  28. Villaschi S., Spagnoli L. G. Autoradiographic and ultrastructural studies on the human fibro-atheromatous plaque. Atherosclerosis. 1983 Jul;48(1):95–100. doi: 10.1016/0021-9150(83)90020-5. [DOI] [PubMed] [Google Scholar]
  29. Yui S., Sasaki T., Araki N., Horiuchi S., Yamazaki M. Induction of macrophage growth by advanced glycation end products of the Maillard reaction. J Immunol. 1994 Feb 15;152(4):1943–1949. [PubMed] [Google Scholar]
  30. Yui S., Sasaki T., Miyazaki A., Horiuchi S., Yamazaki M. Induction of murine macrophage growth by modified LDLs. Arterioscler Thromb. 1993 Mar;13(3):331–337. doi: 10.1161/01.atv.13.3.331. [DOI] [PubMed] [Google Scholar]
  31. Yui S., Ubukata K., Hodono K., Kitahara M., Mimaki Y., Kuroda M., Sashida Y., Yamazaki M. Macrophage-oriented cytotoxic activity of novel triterpene saponins extracted from roots of Securidaca inappendiculata. Int Immunopharmacol. 2001 Oct;1(11):1989–2000. doi: 10.1016/s1567-5769(01)00126-6. [DOI] [PubMed] [Google Scholar]
  32. Yui S., Yamazaki M. Induction of macrophage growth by effete cells. J Leukoc Biol. 1986 May;39(5):489–497. doi: 10.1002/jlb.39.5.489. [DOI] [PubMed] [Google Scholar]
  33. Zou H., Li Y., Liu X., Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999 Apr 23;274(17):11549–11556. doi: 10.1074/jbc.274.17.11549. [DOI] [PubMed] [Google Scholar]
  34. van Rooijen N., Sanders A. Elimination, blocking, and activation of macrophages: three of a kind? J Leukoc Biol. 1997 Dec;62(6):702–709. doi: 10.1002/jlb.62.6.702. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES