Skip to main content
Log in

Effects of Korean Mistletoe Lectin(Viscum album coloratum) on Proliferation and Cytokine Expression in Human Peripheral Blood Mononuclear Cells and T-Lymphocytes

  • Drug Efficacy and Safety
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The anti-cancer activity of mistletoe has been ascribed to a combination of cytotoxic and immunological effects. We previously showed that Korean mistletoe lectin(Viscum album L.var. coloratum agglutinin, VCA) can stimulate IFN-γ production and modulate proliferation in murine splenocytes. In this study, we investigated the effects of VCA on human peripheral blood mononuclear cells (hPBMC) and T-lymphocytes. The addition of VCA resulted in a significant inhibition of proliferation at higher concentrations (at 2–8 ng/mL, 1–8 ng/mL in hPBMC and T-lymphocytes, respectively) but an induction at lower concentrations (at 4–16 pg/mL, 4–32 pg/mL in hPBMC and T-lymphocytes, respectively). Further studies were carried out to determine if the pro-proliferative or anti-proliferative activity exhibited by VCA was correlated with apoptosis and cytokine secretion. As a result, the apoptotic cell number increased to 26% after 48 h of VCA treatment (10 ng/mL) in the presence of anti-CD3/CD28 antibodies. On the other hand, without anti-CD3/CD28 antibody stimulants, VCA did not arrest cell cycle. In addition, it was shown that VCA could induce IL-2 secretion was dose-dependently increased by VCA in stimulated (anti-CD3/CD28 antibodies) (at 0.25-2 ng/mL) and non-stimulated (at 3–25 pg/mL) human T-lymphocytes. Also, at low and non-toxic concentrations of VCA, the RT-PCR result confirmed the release of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8, and IFN-γ. These data may suggest new perspective to modulate the balance between cell growth, cytokine production and programmed cell death therapeutically.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

CD:

cluster of differentiation

cpm:

counts per minute

CTCM:

complete tissue culture medium

ELISA:

enzyme-linked immunosorbent assay

FACS:

florescence activated cell sorting

FCS:

fetal calf serum

HU:

haemagglutinating unit

IL:

interleukin

IFN:

interferon

PBMC:

peripheral blood mononuclear cell

SDS-PAGE:

sodium dodecyl sulfate polyacrylamide gel electrophoresis

VAA:

Viscum album L.var agglutinin

VCA:

Viscum album Lvar coloratum agglutinin

References

  • Alenzi, F. Q., Links between apoptosis, proliferation and the cell cycle.Br. J. Biomed. Sci., 61, 99–101 (2004).

    PubMed  CAS  Google Scholar 

  • Barltrop, J. A., Owen, T. C, Cory, A. H., and Cory, J., G, 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfo- pheynyl) tetrazolium, innersalt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water-soluble formazans as cell- viability indicators.Bioorg. Med. Chem. Lett., 1, 611 (1991).

    Article  CAS  Google Scholar 

  • Büssing, A., Mistletoe therapy and immunological research. Anticancer Drugs, 8 Suppl 1, S65 (1997).

    Article  PubMed  Google Scholar 

  • Büssing, A., Suzart, K., Bergmann, J., Pfüller, U., and Schweizer, K., Induction of apoptosis in human lymphocytes treated withViscum album L. is mediated by the mistletoe lectins.Cancer Lett., 109, 33–38(1996).

    Article  Google Scholar 

  • Cory, A. H., Owen, T. C, Barltrop, J. A., and Cory, J. G, Use of an aqueous soluble tetrazolium formazan assay for cell- growth assays in culture.Cancer Commun., 3, 207–212 (1991).

    PubMed  CAS  Google Scholar 

  • Elsasser-Beile, U., Voss, M., Schuhle, R., and Wetterauer, U., Biological Effects of Natural and Recombinant Mistletoe Lectin and an Aqueous Mistletoe Extract on Human Monocytes and LymphocytesIn Vitro.J. Clin. Lab. Anal., 14, 255–259 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Fernandez, T., Wagner, M. L., Varela, B. G, Ricco, R. A., Hajos, S. E., Gurni, A. A., and Alvarez, E., Study of an Argentine Mistletoe, the hemiparasiteLigaria cuneifolia (R. et P.) Tiegh. (Loranthaceae).J. Ethnopharmacol., 62, 25–34 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Franz, H., Ziska, P., and Kindt, A. Isolation and properties of three lectins from mistletoe (Viscum album L).Biochem. J., 195,481–484(1981).

    PubMed  CAS  Google Scholar 

  • Frauwirth, K. A., Riley, J. L, Harris, M. H., Parry, R. V, Rathmell, J. C, Plas, D. R., Elstrom, R. L, June, C. H., and Thompson, C. B., The CD28 signaling pathway regulates glucose metabolism.Immunity, 16, 769–777(2002).

    Article  PubMed  CAS  Google Scholar 

  • Gleichmann, E., Kimber, I., and Purchase, I. F., Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system. A discussion.Arch. Toxicol., 63, 257–273 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Hajto, T, Hostanska, K., Fischer, J., and Sailer, R., Immunomo- dulatory effects ofViscum album agglutinin-l on natural immunity.Anticancer Drugs, 8, 543–546 (1997).

    Article  Google Scholar 

  • Hajto, T., Hostanska, K., Frei, K., Rordorf, C, and Gabius, H. J., Increased secretion of tumor necrosis factor a, interleukin 1, and interleukin 6 by human mononuclear cells exposed to â- galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res., 50, 3322–3326 (1990).

    PubMed  CAS  Google Scholar 

  • Hajto, T., Hostanska, K., Weber, K., Zinke, H., Fischer, J., Mengs, U., Lentzen, H., and Sailer, R., Effect of a recombinant lectin, Viscum album agglutinin on the secretion of interleukin-12 in cultured human peripheral blood mononuclear cells and on NK-cell-mediated cytotoxicity of rat splenocytes in vitro and in vivo.Nat. Immun., 16, 34–46 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Hellerstein, M. K. and McCune, J. M., T cell turnover in HIV-1 disease.Immunity, 7, 583–589 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Hostanska, K., Hajto, T., Spagnoli, G C, Fischer, J., Lentzen, H., and Hermann, R., A plant lectin derived fromViscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells.Nat. Immun., 14, 295–304 (1995).

    PubMed  CAS  Google Scholar 

  • Hostanska, K., Hajto, T, Weber, K., Fischer, J., Lentzen, H., Sutterlin, B., and Sailer, R., A natural immunity-activating plant lectin,Viscum album agglutinin-1, induces apoptosis in human lymphocytes, monocytes, monocytic THP-1 cells, and murine thymocytes.Nat. Immun., 15, 295–311 (1996).

    PubMed  CAS  Google Scholar 

  • Iwahash, H., Eguchi, Y, Yasuhara, N., Hanafusa, T., Matsuzawa, Y, and Tsujimoto, Y, Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy.Nature, 390, 413–417 (1997).

    Article  Google Scholar 

  • Janeway Jr., C. A., Travers, P., Walport, M., and Shlomchik, M. J., General properties of armed effector T cells. In Austin, P., and Lawrence, E. (Eds.). Immunobiology: the immune system in health and disease. 5th ed. Garland Publishing, New York, NY, pp. 318–319 (2001).

    Google Scholar 

  • Kovacs, E., Serum levels of IL-12 and the production of IFN- gamma, IL-2 and IL-4 by peripheral blood mononuclear cells (PBMC) in cancer patients treated withViscum album extract.Biomed. Pharmacother., 54, 305–10 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Lavastre, Y, Cavalli, H., Ratthe, C, and Girard, D., Anti- inflammatory effect ofViscum album agglutinin-l (VAA-I): induction of apoptosis in activated neutrophils and inhibition of lipopolysaccharide-induced neutrophilic inflammationin vivo.Clin. Exp. Immunol., 137, 272–278 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Lavastre, V., Pelletier, M., Saller, R., Hostanska, K., and Girard, D., Mechanisms involved in spontaneous and Viscum album agglutinin-l-induced human neutrophil apoptosis: Viscum album agglutinin-l accelerates the loss of antiapoptotic Mcl-1 expression and the degradation of cytoskeletal paxillin and vimentin proteins via caspases.J. Immunol., 168, 1419–1427 (2002).

    PubMed  CAS  Google Scholar 

  • Lyu, S. Y, Choi, S. H., and Park, W. B., Korean mistletoe lectin- induced apoptosis in hepatocarcinoma cells is associated with inhibition of telomerase via mitochondrial controlled pathway independent of p53.Arch. Pharm. Res., 25, 93–101 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Lyu, S. Y, Park, S. M., Choung, B. Y, and Park, W. B., Comparative study of Korean(Viscum album var.coloratum) and European mistletoes(Viscum album).Arch. Pharm. Res., 23, 592–598 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Lyu, S. Y, Park, W. B., Choi, K. H., and Kim, W. H., Involvement of caspase-3 in apoptosis induced byViscum album var.coloratum agglutinin in HL-60 cells.Biosci. Biotechnol. Biochem., 65, 534–541 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Männel, D. N., Becker, H., Gundt, A., Kist, A., and Franz, H., Induction of tumor necrosis factor expressed by a lectin fromViscum album.Cancer Immunol. Immunother, 33, 177–182 (1991).

    Article  PubMed  Google Scholar 

  • Okuda, T, Yoshida, T, Chen, X. M., Xie, J. X., and Fukushima, M., Corianin from Coriaria japonica A. Gray and sesquiterpene lactones fromLoranthus parasiticus Merr used for treatment of schizophrenia.Chem. Pharm. Bull., 35, 182–187 (1987).

    PubMed  CAS  Google Scholar 

  • Park, J. H., Hyun, C. K., and Shin, H. K., Cytotoxicity of heat- treated Korean mistletoe.CancerLett., 126, 43–48 (1998a).

    CAS  Google Scholar 

  • Park, W. B., Han, S. K., Lee, M. H., and Han, K. H., Isolation and characterizaton of lectins from stem and leaves of Korean mistletoe(Viscum album L. var.coloratum) by affinity chromatography.Arch. Pharm. Res., 20, 306–312 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Park, W. B., Ju, Y J., and Han, S. K., Isolation and characterization of â-galactoside specific lectin from Korean mistletoe(Viscum album L varcoloratum) with lactose-BSA-Sepharose 4B and changes of lectin conformation.Arch. Pharm. Res., 21, 429–435 (1998b).

    Article  PubMed  CAS  Google Scholar 

  • Park, W. B., Ju, Y J., and Han, S. K., Isolation and characterization of beta-galactoside specific lectin from Korean mistletoe(Viscum album var.coloratum) with lactose-BSA- sepharose 4B and changes of lectin conformation.Arch. Pharm. Res., 21, 429–435 (1998c).

    Article  PubMed  CAS  Google Scholar 

  • Park, W. B., Lyu, S. Y, Kim, J. H., Choi, S. H., Chung, H. K., Ahn, S. H., Hong, S. Y, Yoon, T. J., and Choi, M. J., Inhibition of tumor growth and metastasis by Korean mistletoe lectin is associated with apoptosis and antiangiogenesis.Cancer Biother. Radiopharm., 16, 439–447 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Riss, T. L. and Moravee, R. A., Comparison of MTT, XTT, and a novel tetrazolium compound MTS forin vitro proliferation and chemosensitivity assays.Mol. Biol. Cell, 3, A184-A184 (1992).

    Google Scholar 

  • Saikumar, P., Dong, Z., Weinberg, J. M., and Venkatachalam, M. A., Mechanisms of cell death in hypoxia/reoxygenation injury.Oncogene, 17, 3341–3349 (1998).

    Article  PubMed  Google Scholar 

  • Savoie, A., Lavastre, V, Pelletier, M., Hajto, T., Hostanska, K., and Girard, D., Activation of human neutrophils by the plant lectin Viscum album agglutinin-l: modulation of de novo protein synthesis and evidence that caspases are involved in induction of apoptosis.J. Leukoc. Biol., 68, 845–53 (2000).

    PubMed  CAS  Google Scholar 

  • Stein, G M., Pfuller, U., Schietzel, M., and Bussing, A., Intracellular expression of IL-4 and inhibition of IFN-gamma by extracts from European mistletoe is related to induction of apoptosis.Anticancer Res., 20, 2987–2994 (2000).

    PubMed  CAS  Google Scholar 

  • Thomaidou, D., Mione, M. C, Cavanagh, J. R, and Parnavelas, J. G., Apoptosis and its relation to the cell cycle in the developing cerebral cortex.J. Neurosci., 17, 1075–1085 (1997).

    PubMed  CAS  Google Scholar 

  • Thompson, C. B., Apoptosis in the pathogenesis and treatment of disease.Science, 3, 141–144 (1995).

    Google Scholar 

  • Wu, A. M., Song, S. H., Hwang, P. Y, Wu, J. H., and Pfüller, U., Interaction of mistletoe toxic lectin-l with sialoglycoproteins.Biochem. Biophys. Res. Commun., 214, 396–402 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Yoon, T. J., Yoo, Y. C, Choi, O. B., Do, M. S., Kang, T. B., Lee, S. W., Azuma, I., and Kim, J. B., Inhibitory effect of Korean mistletoe(Viscum album coloratum) extract on tumour angiogenesis and metastasis of haematogenous and nonhaematogenous tumour cells in mice.Cancer Lett., 97, 83–91 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Yoon, T. J., Yoo, Y. C, Kang, T. B., Her, E., Kim, S. H., Kim, K., Azuma, I., and Kim, J. B., Cellular and humoral adjuvant activity of lectins isolated from Korean mistletoe(Viscum album coloratum).Int. Immunopharmacol., 1, 881 -889 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Yoon, T. J., Yoo, Y C, Kang, T. B., Shimazaki, K., Song, S. K., Lee, K. H., Kim, S. H., Park, C. H., Azuma, I., and Kim, J. B., Lectins isolated from Korean mistletoe(Viscum album coloratum) induce apoptosis in tumor cells.Cancer Lett., 136,33–40(1999).

    Article  PubMed  CAS  Google Scholar 

  • Yoon, T. J., Yoo, Y. C, Kang, T. B. B., Y J., Huh, C. S., Song, S. K., Lee, K. H., Azuma and Kim, J. B.,Prophylactic effect of Korean mistletoe(Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity.Int. J. Immunopharmacol., 20, 163–172 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Zee Cheng, R. K. Y, Anticancer research on Loranthaceae plants.Drugs Future, 22, 519–530 (1997).

    CAS  Google Scholar 

  • Zhu, S. H., Effect of Viscum coloratum (Kom) Nakai on change in the cyclic nucleotides in ischemic myocardium.Chung Hsi / Chieh Ho Tsa Chih, 4, 548–551 (1984).

    CAS  Google Scholar 

  • Zhu, W. M., Xie, L, and Zheng, S. Y, Mechanism of the antiplatelet aggregative activity.Yiyao Gongye, 16, 257–261 (1985).

    CAS  Google Scholar 

  • Zornig, M., Hueber, A. O., Baum, W., and Evan, G, Apoptosis regulators and their role in tumorigenesis.Biochim. Biophys. Acta., 1551, F1-F37 (2001).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Won-Bong Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lyu, SY., Park, WB. Effects of Korean Mistletoe Lectin(Viscum album coloratum) on Proliferation and Cytokine Expression in Human Peripheral Blood Mononuclear Cells and T-Lymphocytes. Arch. Pharm. Res. 30, 1252–1264 (2007). https://doi.org/10.1007/BF02980266

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02980266

Key words

Navigation