Skip to main content
Log in

Liposome-encapsulated muramyl tripeptide up-regulates monocyte chemotactic and activating factor gene expression in human monocytes at the transcriptional and post-transcriptional levels

  • Original Articles
  • Liposome-Encapsulated Muramyl Tripeptide, MCAF, mRNA, Monocyte
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a novel immune modulator that is now under investigation against metastatic melanoma and osteosarcoma. We have already reported that L-MTP-PE induced monocyte-mediated tumoricidal activity and up-regulation of the tumor necrosis factor and interleukin-1 (IL-1) in vivo and in vitro. We now demonstrate that L-MTP-PE also induces monocyte chemotactic and activating factor (MCAF) mRNA expression at both the transcriptional and post-transcriptional levels. Monocyte chemotactic activity was also present in the supernatants of L-MTP-PE-stimulated cells. In monocytes, the increased expression of MCAF was induced rapidly (by 2 h) but was short-lived. By 4 h, MCAF mRNA had decreased to background level. We found no change in MCAF mRNA levels in lymphocytes exposed to L-MTP-PE. We therefore conclude that L-MTP-PE selectively up-regulates MCAF expression in monocytes and that MCAF may play a role in the tumoricidal and immune-stimulating activity of L-MTP-PE.

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

References

  1. Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT (1992) Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA 89: 5371

    PubMed  Google Scholar 

  2. Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A (1983) Regulation of macrophage content of neoplasms by chemoattractants. Science 220: 210

    PubMed  Google Scholar 

  3. Bottazzi B, Polentarutti N, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A (1983) Chemotactic activity for mononuclear phagocytes of culture supernatants from murine and human tumor cells evidence for a role in the regulation of macrophage content of neoplastic tissues. Int J Cancer 31: 55

    PubMed  Google Scholar 

  4. Bottazzi B, Ghezzi P, Taraboletti G, Salmona M, Colombo N, Bonazzi C, Mangioni C, Mantovani A (1985) Tumor-derived chemotactic factor(s) from human ovarian carcinoma: evidence for a role in the regulation of the macrophage content of neoptic tissues. Int J Cancer 36: 167

    PubMed  Google Scholar 

  5. Bottazzi B, Erba E, Nobili N, Fazioli F, Rambaldi A, Mantovani A (1990) A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcoma. J Immunol 144: 2409

    PubMed  Google Scholar 

  6. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A (1992) Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 148: 1280

    PubMed  Google Scholar 

  7. Cleveland DW, Lopata MA, McDonald RJ, Cowan NJ, Ruther WJ, Kirschner M (1980) Number and evolutionary conservation of a- and b-tubulin and b- and g-actin genes using specific cloned cDNA probes. Cell 20: 95

    PubMed  Google Scholar 

  8. Colotta F, Borre A, Wang JM, Tattanelli M, Maddalena F, Polentarutti N, Peri G, Mantovani A (1992) Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. J Immunol 148: 760

    PubMed  Google Scholar 

  9. Evans R, Haskill S (1983) Activities of macrophages within and peripheral to the tumor mass. In: Herberman R.B., Friedman H., (eds) The reticuloendothelial system: a comprehensive treatise, vol 5 Cancer, Plenum, New York, p. 155

    Google Scholar 

  10. Falk W, Goodwin RH, Leonard EJ (1980) A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods 33: 239

    PubMed  Google Scholar 

  11. Fidler IJ, Poste G (1982) Macrophage-mediated destruction of malignant tumor cells and new strategies for the therapy of metastatic disease. Springer Semin Immunopathol 5: 164

    Google Scholar 

  12. Fidler IJ, Sone S, Fogler WE, Barnes Z (1981) Eradication of spontaneous metastasis and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78: 1680

    PubMed  Google Scholar 

  13. Fort P, Marty L, Piechaczyk M, Sabrouty SE, Dani C, Jeanteur P, Blanchard JM (1985) Various rat adult tissues express only one major mRNA species from the glyceraidehyde-3-phosphatidehydrogenase multigene family. Nucleic Acids Res 13: 1431

    PubMed  Google Scholar 

  14. Fujimaki W, Balch CM, Ross MI, Augustus LB, Itoh K, Fidler IJ, Griffin JR, Kleinerman ES (1992) Pilot study of liposomal muramyl tripeptide in melanoma patients: cytokine production and activation of monocytes and lymphocytes (abstract 1973) Proc Am Assoc Cancer Res 33: 331

    Google Scholar 

  15. Furutani Y, Nomura HM, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen G, Oppenheim JJ, Matsushima K (1989) Cloning and sequencing of cDNA for human monocyte chemotactic and activating factor (MCAF). Biochem Biophys Res Commun 159: 244

    Google Scholar 

  16. Jiang Y, Beller DI, Frendyl G, Graves DT (1992) Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 148: 2423

    PubMed  Google Scholar 

  17. Kleinerman ES, Erickson KL, Schroit AJ, Fogler WE, Fidler IJ (1983) Activation of tumoricidal properties in human blood monocytes by liposomes containing muramyl lipophilic tripeptide. Cancer Res 43: 2010

    PubMed  Google Scholar 

  18. Kleinerman ES, Murray JL, Snyder JS, Cunningham JE, Fidler IJ (1989) Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposome containing muramyl tripeptide phosphatidylethanolamine. Cancer Res 49: 4665

    PubMed  Google Scholar 

  19. Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N (1992) Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol 10: 1310

    PubMed  Google Scholar 

  20. Kleinerman ES, Raymond AK, Bucana CD, Jaffe N, Harris MB, Krakoff IH, Benjamin R, Fidler IJ (1992) Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid). Cancer Immunol Immunother 34: 211

    PubMed  Google Scholar 

  21. Kleinerman ES, Asano T, Gano JB, Johnston D, Benjamin RS, Jaffe N (1993) Liposome-encapsulated MTP-PE: a novel biologic for cancer therapy (abstract NZ030). J Cell Biochem [Abstract Suppl] 170: 99

    Google Scholar 

  22. Leonard EJ, Yoshimura T (1990) Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 11: 97

    PubMed  Google Scholar 

  23. Liebes L, Walsh CM, Chachoua A, Oratz R, Richards D, Hochster H, Peace D, Marino D, Alba S, Le Sher D, Blum RH, Vilcek J (1992) Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma. J Natl Cancer Inst 84: 694

    PubMed  Google Scholar 

  24. MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Howard PE (1989) Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 81: 935

    PubMed  Google Scholar 

  25. Maeda M, Knowles RD, Kleinerman ES (1991) Muramyl tripeptide phosphatidylethanolamine (MTP-PE) encapsulated in liposomes stimulates monocyte production of tumor necrosis factor and interleukin-1 in vivo. Cancer Commun 3: 313

    PubMed  Google Scholar 

  26. Mantovani A (1990) Tumor-associated macrophages. Curr Opin Immunol 2: 689

    Google Scholar 

  27. Matsushima K, Morishita K, Yoshimura T, Lavus S, Kobayashi Y, Lew W, Appella E, Kung H, Leonard EJ, and Oppenheim JJ (1988) Molecular cloning of a human monocyte derived neutrophil chemotactic and activating factor (MDNCF) and the induction of MDNCF mRNA by interleukin-1 and Tumor necrosis factor. J Exp Med 167: 1883

    PubMed  Google Scholar 

  28. Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ (1989) Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 169: 1485

    PubMed  Google Scholar 

  29. McBride WH (1986) Phenotype and functions of intratumoral macrophages. Biochim Biophys Acta 865: 27

    PubMed  Google Scholar 

  30. Murray JL, Kleinerman ES, Cunnigham JE, Tatom JR, Andrejcio K, Lepe-Zuniga J, Lamki LM, Rosenblum MG, Frost H, Gutterman JU, Fidler IJ, Krakoff IH (1989) Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol 7: 1915

    PubMed  Google Scholar 

  31. Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K (1991) Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu Rev Immunol 9: 617

    PubMed  Google Scholar 

  32. Rollins BJ, Sunday ME (1991) Suppression of tumor formation in vitro by expression of the JE gene in malignant cells. Mol Cell Biol 11: 3125

    PubMed  Google Scholar 

  33. Rollins BJ, Walz A, Baggiolini M (1991) Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood 78: 1112

    PubMed  Google Scholar 

  34. Schroit AJ, Fidler IJ (1982) Effect of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42: 161

    PubMed  Google Scholar 

  35. Urba WJ, Hartmann LC, Longo DL, Steis RG, Smith II, JW, Kedar I, Creekmore S, Sznol M, Conlon K, Kopp WC, Huber C, Herold M, Alvord WG, Snow S, Clark JW (1990) Phase I and immunomodulatory study of a muramyl peptide, muramyl tripeptide phosphatidylethanolamine. Cancer Res 50: 2979

    PubMed  Google Scholar 

  36. Zachariae OC, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, Matsushima K (1990) Properties of monocytic chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med 171: 2177

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Asano, T., Matsushima, K. & Kleinerman, E.S. Liposome-encapsulated muramyl tripeptide up-regulates monocyte chemotactic and activating factor gene expression in human monocytes at the transcriptional and post-transcriptional levels. Cancer Immunol Immunother 38, 16–22 (1994). https://doi.org/10.1007/BF01517165

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01517165

Key words

Navigation