Activation of macrophages by ether analogues of lysophospholipids


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.

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  1. 1.

    Andreesen R, Moddell M, Weltzien HU, Common HH, Lori GW, Munder PG (1978) Selective destruction of human leukemic cells by alkyl-lysophospholipids. Cancer Res 38:3894

    Google Scholar 

  2. 2.

    Babior BM, Cohen HJ (1981) Measurement of neutrophil function: phagocytosis, degranulation, the respiratory burst and bacterial killing. In: Cline MJ (ed) Methods in hematology: leukocyte function. Churchill Livingstone, New York, p 1

    Google Scholar 

  3. 3.

    Baumann WJ, Mangold HK (1964) Reaction of aliphatic methansulfonates. I. Synthesis of long-chain glyceryl-(1) ethers. J Org Chem 296:3055

    Google Scholar 

  4. 4.

    Berdel WE, Bausert WR, Weltzien HU, Modolell ML, Widmann KH, Munder PG (1980) The influence of alkyl-lysophospholipids and lysophospholipid-activated macrophages on the development of metastasis of 3 Lewis lung carcinoma. Eur J Cancer 16:1199

    Google Scholar 

  5. 5.

    Berdel WE, Fink U, Egger B, Reichert A, Munder PG, Raststetter J (1981) Inhibition by alkyl-lysophospholipids of tritiated thymidine uptake in cells of human malignant urologic tumors. J Natl Cancer Inst 66:813

    Google Scholar 

  6. 6.

    Bianco C, Griffin RM, Silverstein SC (1975) Studies of macrophage complement receptors. Alteration of receptor function upon macrophage activation. J Exp Med 141:1278

    Google Scholar 

  7. 7.

    Brissette JL, Cabacungan EA, Pieringer RA (1986) 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 261:6338

    Google Scholar 

  8. 8.

    Chien KR, Abrams J, Serioni A, Martin JT, Farber JL (1978) Accelerated phospholipid degradation and association membrane dysfunction in irreversible ischemic liver cell injury. J Biol Chem 253:4809

    Google Scholar 

  9. 9.

    Cohn ZA, Benson B (1965) The differentiation of mononuclear phagocytes, morphology, cytochemistry, and biochemistry. J Exp Med 121:153

    Google Scholar 

  10. 10.

    Doe WF, Henson PM (1978) Macrophage stimulation by bacterial lipopolysaccharides. I. Cytolytic effect on tumor target cells. J Exp Med 148:544

    Google Scholar 

  11. 11.

    Estensen RD, White JG, Holmes B (1974) Specific degranulation of human polymorphonuclear leukocytes. Nature 248:347

    Google Scholar 

  12. 12.

    Griffin FM, Silverstein SC (1974) Segmental response of the macrophage plasma membrane to a phagocytic stimulus. J Exp med 139:323

    Google Scholar 

  13. 13.

    Mangold HK (1972) Biological effects and biomedical applications of alkoxylipids. In: Ether lipids. Academic Press, New York, NY, p 158

    Google Scholar 

  14. 14.

    Mantovani B, Robinovitch M, Nussensweig V (1972) Phagocytosis of murine complexes by macrophages. Different roles of the macrophage receptor sites for complement (C3) and for immunoglobulin (IgG). J Exp Med 135:780

    Google Scholar 

  15. 15.

    Modelell M, Munder PG (1972) The action of purified phospholipase B in inflammation and immunity. Int Arch Allergy Appl Immunol 43:724

    Google Scholar 

  16. 16.

    Modelell M, Andreesen R, Pahlkes W, Brugger U, Munder PG (1979) Disturbance of phospholipid metabolism during selective destruction of tumor cells induced by alkylphospholipids. Cancer Res 38:4681

    Google Scholar 

  17. 17.

    Munder PG, Modelell M, Andreesen R, Weltzien HU, Westphal O (1980) Lysophosphatidylcholine (Lysolecithin) and its synthetic analogs, immunomodulating and other biological effects. In: Chedid L, Miesher PA, Mueller-Eberhard HJ (eds) Immunomodulating. Springer Semin Immunopathol Vol. 2 No. 1–2. Springer-Verlag, Berlin, p 177

    Google Scholar 

  18. 18.

    Ngwenya BZ, Yamamoto N (1985) Activation of peritoneal macrophages by lysophosphatidylcholine. Biochim Biophys Acta 839:9

    Google Scholar 

  19. 19.

    Ngwenya BZ, Yamamoto N (1986) Effects of inflammation products on immune system: Lysophosphatidylcholine activates macrophages. Cancer Immunol Immunother 21:174

    Google Scholar 

  20. 20.

    Ottolenghi A, Kocan AA, Weatherly NF, Larsh JE (1975) Nippostrongylus brasiliensis: Phospholipase in nonsensitized and sensitized rats after challenge. Exp Parasitol 38:96

    Google Scholar 

  21. 21.

    Paltauf F (1983) Ether lipids as substrates for lypolytic enzymes. In: Ether lipids. Biochemical and biomedical aspects. Academic Press, New York, NY, p 211

    Google Scholar 

  22. 22.

    Runge MH, Andreesen R, Pfleiderer A, Munder PG (1980) Destruction of human solid tumors by alkyl lysophospholipids. J Natl Cancer Inst 64:1301

    Google Scholar 

  23. 23.

    Shaw DR, Griffin FM (1984) 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 84:317

    Google Scholar 

  24. 24.

    Snyder F, Wood R (1968) The occurrence and metabolism of alkyl and alk-1-enly ethers of glycerol in transplantable rat and mouse tumors. Cancer Res 28:972

    Google Scholar 

  25. 25.

    Snyder F, Wood R (1969) Alkyl and alk-1-enly ethers of glycerol in lipids from normal and neoplastic human tissues. Cancer Res 29:251

    Google Scholar 

  26. 26.

    Storme GA, Berdel WE, Von Blitterswijk WJ, Bruyncel EA, De Bruyne GK, Marcel MM (1985) Antiinvasive effect of racemic 1–0-octadeyl-2–0-methylglycero-3-phosphocholine on M4 mouse fibrosarcoma cells in vitro. Cancer Res 45:351

    Google Scholar 

  27. 27.

    Tabor DR, Saluk PH (1981) The functional heterogenecity of murine-resident macrophages to a chemotactic signal and induction of C3b receptor mediated ingestion. Immunol Lett 3:371

    Google Scholar 

  28. 28.

    Ved HS, Gustow E, Mahadevan V, Pieringer RA (1984) Dodecylglycerol. A new type of antibacterial agent which stimulates autolysin in Streptococcus faicium ATCC9790. J Biol Chem 259:8115

    Google Scholar 

  29. 29.

    Ved HS, Gustow E, Pieringer RA (1984) The involvement of the proteinase of Streptococcus faecium ATCC9790 in the stimulation of its autolysin activity of dodecylglycerol. J Biol Chem 259:8122

    Google Scholar 

  30. 30.

    Ved HS, Gustow E, Pieringer RA (1984) Inhibition of peptidoglycan synthesis of Streptococcus faecium ATCC9790 and Streptococcus mutans BHT by the antibacterial agent dodecylglycerol. Biosci Rep 4:659

    Google Scholar 

  31. 31.

    Weltzien HU (1979) Catalytic and membrane-perturbing properties of lysophosphatidyl-choline. Biochim Biophys Acta 559:259

    Google Scholar 

  32. 32.

    Weltzien HU, Munder PG (1983) Synthetic alkyl analogs of lysophosphatidylcholine: Membrane activity, metabolic study and effects on immune response and tumor growth. In: Ether lipids. Biochemical and biomedical aspects. Academic Press, New York, p 277

    Google Scholar 

  33. 33.

    Weltzien HU, Arnold B, Kaloff HG (1976) 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 455:56

    Google Scholar 

  34. 34.

    Woelk H (1974) 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 59:1278

    Google Scholar 

  35. 35.

    Wrigley DM, Saluk PH (1981) Induction of C3b-mediated phagocytosis in macrophages by distinct population of lipopolysaccharide-stimulated lymphocytes. Infect Immun 34:780

    Google Scholar 

  36. 36.

    Wykle RL, Schremmer JM (1974) A phospholipases D pathway in metabolism of ether linked lipids in brain microsomes. J Biol Chem 249:1742

    Google Scholar 

  37. 37.

    Wykle RL, Kraemer WF, Schremmer JM (1977) Studies of lysophospholipase D of rat liver and other tissues. Arch Biochem Biophys 184:149

    Google Scholar 

  38. 38.

    Wykle RL, Kraemer WF, Schremmer JM (1980) Specificity of lysophospholipase D. Biochim Biophys Acta 619:58

    Google Scholar 

  39. 39.

    Yamamoto N, Ngwenya BZ (1987) Activation of mouse peritoneal macrophages by lysophospholipids and ether derivatives of neutral lipids and phospholipids. Cancer Res 47:2008–2013

    Google Scholar 

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Correspondence to Nobuto Yamamoto.

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Yamamoto, N., Ngwenya, B.Z., Sery, T.W. et al. Activation of macrophages by ether analogues of lysophospholipids. Cancer Immunol Immunother 25, 185–192 (1987).

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  • Superoxide
  • Chemotherapeutic Agent
  • Rapid Decrease
  • Peritoneal Macrophage
  • Retinoblastoma