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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1987 Nov;25(3):185–192. doi: 10.1007/BF00199146

Activation of macrophages by ether analogues of lysophospholipids

Nobuto Yamamoto 1,, Benjamin Z Ngwenya 1, Theodore W Sery 2, Ronald A Pieringer 3
PMCID: PMC11038200  PMID: 2824051

Abstract

Inflammation processes cause activation of phospholipase A in plasma membranes resulting in the production of various lysophospholipids. Treatment of mice with L-α-lysophosphatidyl-DL-glycerol (lyso-Pg) resulted in an enhanced ingestion activity of peritoneal macrophages as did other lysophospholipids. However, lyso-Pg is rather toxic as indicated by a rapid decrease in macrophage activity 3 days after treatment while macrophage activity of lysophosphatidylcholine-treated mice continued to increase at least up to the 6th day after treatment. Alkyl-lysophospholipid derivatives, racemic 1-0-octadecyl-2-methylglycero-3-phosphocholine and -phosphoethanolamine stimulated mouse macrophages for Fc-mediated ingestion. Decomposed products of alkyl-lysophospholipids, alkylglycerols, were also found to be excellent activators of macrophages not only for ingestion of IgG-coated target cells but also antibody-mediated tumoricidal activity. Macrophages from mice treated with alkylglycerols developed superoxide generating capacity. Furthermore, alkylglycerols were found to be tumoricidal by direct contact with retinoblastoma cells. Therefore, the advantage of the potential application of alkylglycerols as chemotherapeutic agents is that they have dual beneficial effects: potentiation of macrophage activity and cytotoxicity to malignant cells.

Keywords: Superoxide, Chemotherapeutic Agent, Rapid Decrease, Peritoneal Macrophage, Retinoblastoma

References

  • 1.Andreesen R, Moddell M, Weltzien HU, Common HH, Lori GW, Munder PG. Selective destruction of human leukemic cells by alkyl-lysophospholipids. Cancer Res. 1978;38:3894. [PubMed] [Google Scholar]
  • 2.Babior BM, Cohen HJ. Measurement of neutrophil function: phagocytosis, degranulation, the respiratory burst and bacterial killing. In: Cline MJ, editor. Methods in hematology: leukocyte function. New York: Churchill Livingstone; 1981. p. 1. [Google Scholar]
  • 3.Baumann WJ, Mangold HK. Reaction of aliphatic methansulfonates. I. Synthesis of long-chain glyceryl-(1) ethers. J Org Chem. 1964;296:3055. [Google Scholar]
  • 4.Berdel WE, Bausert WR, Weltzien HU, Modolell ML, Widmann KH, Munder PG. The influence of alkyl-lysophospholipids and lysophospholipid-activated macrophages on the development of metastasis of 3 Lewis lung carcinoma. Eur J Cancer. 1980;16:1199. doi: 10.1016/0014-2964(80)90179-6. [DOI] [PubMed] [Google Scholar]
  • 5.Berdel WE, Fink U, Egger B, Reichert A, Munder PG, Raststetter J. Inhibition by alkyl-lysophospholipids of tritiated thymidine uptake in cells of human malignant urologic tumors. J Natl Cancer Inst. 1981;66:813. [PubMed] [Google Scholar]
  • 6.Bianco C, Griffin RM, Silverstein SC. Studies of macrophage complement receptors. Alteration of receptor function upon macrophage activation. J Exp Med. 1975;141:1278. doi: 10.1084/jem.141.6.1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Brissette JL, Cabacungan EA, Pieringer RA. Studies on the antibacterial activity of dodecylglycerol. Its limited metabolism and inhibition of glycerolipid and lipoteichoic acid biosynthesis in Streptococcus mutans BHT. J Biol Chem. 1986;261:6338. [PubMed] [Google Scholar]
  • 8.Chien KR, Abrams J, Serioni A, Martin JT, Farber JL. Accelerated phospholipid degradation and association membrane dysfunction in irreversible ischemic liver cell injury. J Biol Chem. 1978;253:4809. [PubMed] [Google Scholar]
  • 9.Cohn ZA, Benson B. The differentiation of mononuclear phagocytes, morphology, cytochemistry, and biochemistry. J Exp Med. 1965;121:153. doi: 10.1084/jem.121.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Doe WF, Henson PM. Macrophage stimulation by bacterial lipopolysaccharides. I. Cytolytic effect on tumor target cells. J Exp Med. 1978;148:544. doi: 10.1084/jem.148.2.544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Estensen RD, White JG, Holmes B. Specific degranulation of human polymorphonuclear leukocytes. Nature. 1974;248:347. doi: 10.1038/248347a0. [DOI] [PubMed] [Google Scholar]
  • 12.Griffin FM, Silverstein SC. Segmental response of the macrophage plasma membrane to a phagocytic stimulus. J Exp med. 1974;139:323. doi: 10.1084/jem.139.2.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mangold HK. Ether lipids. New York, NY: Academic Press; 1972. Biological effects and biomedical applications of alkoxylipids; p. 158. [Google Scholar]
  • 14.Mantovani B, Robinovitch M, Nussensweig V. Phagocytosis of murine complexes by macrophages. Different roles of the macrophage receptor sites for complement (C3) and for immunoglobulin (IgG) J Exp Med. 1972;135:780. doi: 10.1084/jem.135.4.780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Modelell M, Munder PG. The action of purified phospholipase B in inflammation and immunity. Int Arch Allergy Appl Immunol. 1972;43:724. doi: 10.1159/000230888. [DOI] [PubMed] [Google Scholar]
  • 16.Modelell M, Andreesen R, Pahlkes W, Brugger U, Munder PG. Disturbance of phospholipid metabolism during selective destruction of tumor cells induced by alkylphospholipids. Cancer Res. 1979;38:4681. [PubMed] [Google Scholar]
  • 17.Munder PG, Modelell M, Andreesen R, Weltzien HU, Westphal O. Lysophosphatidylcholine (Lysolecithin) and its synthetic analogs, immunomodulating and other biological effects. In: Chedid L, Miesher PA, Mueller-Eberhard HJ, editors. Immunomodulating. Springer Semin Immunopathol Vol. 2 No. 1–2. Berlin: Springer-Verlag; 1980. p. 177. [Google Scholar]
  • 18.Ngwenya BZ, Yamamoto N. Activation of peritoneal macrophages by lysophosphatidylcholine. Biochim Biophys Acta. 1985;839:9. doi: 10.1016/0304-4165(85)90175-8. [DOI] [PubMed] [Google Scholar]
  • 19.Ngwenya BZ, Yamamoto N. Effects of inflammation products on immune system: Lysophosphatidylcholine activates macrophages. Cancer Immunol Immunother. 1986;21:174. doi: 10.1007/BF00199358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ottolenghi A, Kocan AA, Weatherly NF, Larsh JE. Nippostrongylus brasiliensis: Phospholipase in nonsensitized and sensitized rats after challenge. Exp Parasitol. 1975;38:96. doi: 10.1016/0014-4894(75)90042-9. [DOI] [PubMed] [Google Scholar]
  • 21.Paltauf F. Ether lipids. Biochemical and biomedical aspects. New York, NY: Academic Press; 1983. Ether lipids as substrates for lypolytic enzymes; p. 211. [Google Scholar]
  • 22.Runge MH, Andreesen R, Pfleiderer A, Munder PG. Destruction of human solid tumors by alkyl lysophospholipids. J Natl Cancer Inst. 1980;64:1301. doi: 10.1093/jnci/64.6.1301. [DOI] [PubMed] [Google Scholar]
  • 23.Shaw DR, Griffin FM. Functional characteristics of the macrophage receptors for IgG-Fc and C3: Failure to detect C3 receptor-mediated extracellular cytolysis by mouse peritoneal macrophages. Cell Immunol. 1984;84:317. doi: 10.1016/0008-8749(84)90103-5. [DOI] [PubMed] [Google Scholar]
  • 24.Snyder F, Wood R. The occurrence and metabolism of alkyl and alk-1-enly ethers of glycerol in transplantable rat and mouse tumors. Cancer Res. 1968;28:972. [PubMed] [Google Scholar]
  • 25.Snyder F, Wood R. Alkyl and alk-1-enly ethers of glycerol in lipids from normal and neoplastic human tissues. Cancer Res. 1969;29:251. [PubMed] [Google Scholar]
  • 26.Storme GA, Berdel WE, Von Blitterswijk WJ, Bruyncel EA, De Bruyne GK, Marcel MM. Antiinvasive effect of racemic 1-0-octadeyl-2-0-methylglycero-3-phosphocholine on M4 mouse fibrosarcoma cells in vitro. Cancer Res. 1985;45:351. [PubMed] [Google Scholar]
  • 27.Tabor DR, Saluk PH. The functional heterogenecity of murine-resident macrophages to a chemotactic signal and induction of C3b receptor mediated ingestion. Immunol Lett. 1981;3:371. doi: 10.1016/0165-2478(81)90069-9. [DOI] [PubMed] [Google Scholar]
  • 28.Ved HS, Gustow E, Mahadevan V, Pieringer RA. Dodecylglycerol. A new type of antibacterial agent which stimulates autolysin in Streptococcus faicium ATCC9790. J Biol Chem. 1984;259:8115. [PubMed] [Google Scholar]
  • 29.Ved HS, Gustow E, Pieringer RA. The involvement of the proteinase of Streptococcus faecium ATCC9790 in the stimulation of its autolysin activity of dodecylglycerol. J Biol Chem. 1984;259:8122. [PubMed] [Google Scholar]
  • 30.Ved HS, Gustow E, Pieringer RA. Inhibition of peptidoglycan synthesis of Streptococcus faecium ATCC9790 and Streptococcus mutans BHT by the antibacterial agent dodecylglycerol. Biosci Rep. 1984;4:659. doi: 10.1007/BF01121019. [DOI] [PubMed] [Google Scholar]
  • 31.Weltzien HU. Catalytic and membrane-perturbing properties of lysophosphatidyl-choline. Biochim Biophys Acta. 1979;559:259. doi: 10.1016/0304-4157(79)90004-2. [DOI] [PubMed] [Google Scholar]
  • 32.Weltzien HU, Munder PG. Ether lipids. Biochemical and biomedical aspects. New York: Academic Press; 1983. Synthetic alkyl analogs of lysophosphatidylcholine: Membrane activity, metabolic study and effects on immune response and tumor growth; p. 277. [Google Scholar]
  • 33.Weltzien HU, Arnold B, Kaloff HG. Quantitative studies of lysolecithin mediated hemolysis: Benzylated lysolecithin as a probe to study effects of temperature and red cell species on the hemolytic reaction. Biochim Biophys Acta. 1976;455:56. doi: 10.1016/0005-2736(76)90153-x. [DOI] [PubMed] [Google Scholar]
  • 34.Woelk H. The action of phospholipase A2 in isolated fat cells and specifically labelled 2-acyl-1-alk-1-enyl-and 2-acyl-1-alkyl-SN-glycero-3-phosphorylcholine. Biochem Biophys Res Commun. 1974;59:1278. doi: 10.1016/0006-291x(74)90452-5. [DOI] [PubMed] [Google Scholar]
  • 35.Wrigley DM, Saluk PH. Induction of C3b-mediated phagocytosis in macrophages by distinct population of lipopolysaccharide-stimulated lymphocytes. Infect Immun. 1981;34:780. doi: 10.1128/iai.34.3.780-786.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Wykle RL, Schremmer JM. A phospholipases D pathway in metabolism of ether linked lipids in brain microsomes. J Biol Chem. 1974;249:1742. [PubMed] [Google Scholar]
  • 37.Wykle RL, Kraemer WF, Schremmer JM. Studies of lysophospholipase D of rat liver and other tissues. Arch Biochem Biophys. 1977;184:149. doi: 10.1016/0003-9861(77)90336-8. [DOI] [PubMed] [Google Scholar]
  • 38.Wykle RL, Kraemer WF, Schremmer JM. Specificity of lysophospholipase D. Biochim Biophys Acta. 1980;619:58. doi: 10.1016/0005-2760(80)90242-8. [DOI] [PubMed] [Google Scholar]
  • 39.Yamamoto N, Ngwenya BZ. Activation of mouse peritoneal macrophages by lysophospholipids and ether derivatives of neutral lipids and phospholipids. Cancer Res. 1987;47:2008–2013. [PubMed] [Google Scholar]

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