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. 1994 Jan;38(1):16–22. doi: 10.1007/BF01517165

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

Takeshi Asano 1, Kouji Matsushima 2, Eugenie S Kleinerman 1,✉
PMCID: PMC11038700  PMID: 8299114

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.

Key words: Liposome-encapsulated muramyl tripeptide; MCAF; mRNA, monocyte

References

  • 1.Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT. Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA. 1992;89:5371. doi: 10.1073/pnas.89.12.5371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A. Regulation of macrophage content of neoplasms by chemoattractants. Science. 1983;220:210. doi: 10.1126/science.6828888. [DOI] [PubMed] [Google Scholar]
  • 3.Bottazzi B, Polentarutti N, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A. 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. 1983;31:55. doi: 10.1002/ijc.2910310110. [DOI] [PubMed] [Google Scholar]
  • 4.Bottazzi B, Ghezzi P, Taraboletti G, Salmona M, Colombo N, Bonazzi C, Mangioni C, Mantovani A. 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. 1985;36:167. doi: 10.1002/ijc.2910360207. [DOI] [PubMed] [Google Scholar]
  • 5.Bottazzi B, Erba E, Nobili N, Fazioli F, Rambaldi A, Mantovani A. A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcoma. J Immunol. 1990;144:2409. [PubMed] [Google Scholar]
  • 6.Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol. 1992;148:1280. [PubMed] [Google Scholar]
  • 7.Cleveland DW, Lopata MA, McDonald RJ, Cowan NJ, Ruther WJ, Kirschner M. Number and evolutionary conservation of a- and b-tubulin and b- and g-actin genes using specific cloned cDNA probes. Cell. 1980;20:95. doi: 10.1016/0092-8674(80)90238-x. [DOI] [PubMed] [Google Scholar]
  • 8.Colotta F, Borre A, Wang JM, Tattanelli M, Maddalena F, Polentarutti N, Peri G, Mantovani A. Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. J Immunol. 1992;148:760. [PubMed] [Google Scholar]
  • 9.Evans R, Haskill S. Activities of macrophages within and peripheral to the tumor mass. In: Herberman R.B., Friedman H., editors. The reticuloendothelial system: a comprehensive treatise, vol 5 Cancer. New York: Plenum; 1983. p. 155. [Google Scholar]
  • 10.Falk W, Goodwin RH, Leonard EJ. A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods. 1980;33:239. doi: 10.1016/0022-1759(80)90211-2. [DOI] [PubMed] [Google Scholar]
  • 11.Fidler IJ, Poste G. Macrophage-mediated destruction of malignant tumor cells and new strategies for the therapy of metastatic disease. Springer Semin Immunopathol. 1982;5:164. doi: 10.1007/BF00199794. [DOI] [PubMed] [Google Scholar]
  • 12.Fidler IJ, Sone S, Fogler WE, Barnes Z. Eradication of spontaneous metastasis and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA. 1981;78:1680. doi: 10.1073/pnas.78.3.1680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Fort P, Marty L, Piechaczyk M, Sabrouty SE, Dani C, Jeanteur P, Blanchard JM. Various rat adult tissues express only one major mRNA species from the glyceraidehyde-3-phosphatidehydrogenase multigene family. Nucleic Acids Res. 1985;13:1431. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Fujimaki W, Balch CM, Ross MI, Augustus LB, Itoh K, Fidler IJ, Griffin JR, Kleinerman ES. Pilot study of liposomal muramyl tripeptide in melanoma patients: cytokine production and activation of monocytes and lymphocytes (abstract 1973) Proc Am Assoc Cancer Res. 1992;33:331. [Google Scholar]
  • 15.Furutani Y, Nomura HM, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen G, Oppenheim JJ, Matsushima K. Cloning and sequencing of cDNA for human monocyte chemotactic and activating factor (MCAF) Biochem Biophys Res Commun. 1989;159:244. doi: 10.1016/0006-291x(89)92430-3. [DOI] [PubMed] [Google Scholar]
  • 16.Jiang Y, Beller DI, Frendyl G, Graves DT. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol. 1992;148:2423. [PubMed] [Google Scholar]
  • 17.Kleinerman ES, Erickson KL, Schroit AJ, Fogler WE, Fidler IJ. Activation of tumoricidal properties in human blood monocytes by liposomes containing muramyl lipophilic tripeptide. Cancer Res. 1983;43:2010. [PubMed] [Google Scholar]
  • 18.Kleinerman ES, Murray JL, Snyder JS, Cunningham JE, Fidler IJ. Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposome containing muramyl tripeptide phosphatidylethanolamine. Cancer Res. 1989;49:4665. [PubMed] [Google Scholar]
  • 19.Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol. 1992;10:1310. doi: 10.1200/JCO.1992.10.8.1310. [DOI] [PubMed] [Google Scholar]
  • 20.Kleinerman ES, Raymond AK, Bucana CD, Jaffe N, Harris MB, Krakoff IH, Benjamin R, Fidler IJ. Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid) Cancer Immunol Immunother. 1992;34:211. doi: 10.1007/BF01741788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kleinerman ES, Asano T, Gano JB, Johnston D, Benjamin RS, Jaffe N. Liposome-encapsulated MTP-PE: a novel biologic for cancer therapy (abstract NZ030) J Cell Biochem [Abstract Suppl] 1993;170:99. [Google Scholar]
  • 22.Leonard EJ, Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1) Immunol Today. 1990;11:97. doi: 10.1016/0167-5699(90)90035-8. [DOI] [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. Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma. J Natl Cancer Inst. 1992;84:694. doi: 10.1093/jnci/84.9.694. [DOI] [PubMed] [Google Scholar]
  • 24.MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Howard PE. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst. 1989;81:935. doi: 10.1093/jnci/81.12.935. [DOI] [PubMed] [Google Scholar]
  • 25.Maeda M, Knowles RD, Kleinerman ES. Muramyl tripeptide phosphatidylethanolamine (MTP-PE) encapsulated in liposomes stimulates monocyte production of tumor necrosis factor and interleukin-1 in vivo. Cancer Commun. 1991;3:313. doi: 10.3727/095535491820873740. [DOI] [PubMed] [Google Scholar]
  • 26.Mantovani A. Tumor-associated macrophages. Curr Opin Immunol. 1990;2:689. doi: 10.1016/0952-7915(90)90031-b. [DOI] [PubMed] [Google Scholar]
  • 27.Matsushima K, Morishita K, Yoshimura T, Lavus S, Kobayashi Y, Lew W, Appella E, Kung H, Leonard EJ, Oppenheim JJ. 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. 1988;167:1883. doi: 10.1084/jem.167.6.1883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med. 1989;169:1485. doi: 10.1084/jem.169.4.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.McBride WH. Phenotype and functions of intratumoral macrophages. Biochim Biophys Acta. 1986;865:27. doi: 10.1016/0304-419x(86)90011-9. [DOI] [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. Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. J Clin Oncol. 1989;7:1915. doi: 10.1200/JCO.1989.7.12.1915. [DOI] [PubMed] [Google Scholar]
  • 31.Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K. Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu Rev Immunol. 1991;9:617. doi: 10.1146/annurev.iy.09.040191.003153. [DOI] [PubMed] [Google Scholar]
  • 32.Rollins BJ, Sunday ME. Suppression of tumor formation in vitro by expression of the JE gene in malignant cells. Mol Cell Biol. 1991;11:3125. doi: 10.1128/mcb.11.6.3125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Rollins BJ, Walz A, Baggiolini M. Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood. 1991;78:1112. [PubMed] [Google Scholar]
  • 34.Schroit AJ, Fidler IJ. Effect of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res. 1982;42:161. [PubMed] [Google Scholar]
  • 35.Urba WJ, Hartmann LC, Longo DL, Steis RG, Smith JW, II, Kedar I, Creekmore S, Sznol M, Conlon K, Kopp WC, Huber C, Herold M, Alvord WG, Snow S, Clark JW. Phase I and immunomodulatory study of a muramyl peptide, muramyl tripeptide phosphatidylethanolamine. Cancer Res. 1990;50:2979. [PubMed] [Google Scholar]
  • 36.Zachariae OC, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, Matsushima K. Properties of monocytic chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med. 1990;171:2177. doi: 10.1084/jem.171.6.2177. [DOI] [PMC free article] [PubMed] [Google Scholar]

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