Macrophage Phospholipase A2 Activity and Eicosanoid Production: Studies with Phospholipase A2 Inhibitors in P388D1 Cells

  • Keith B. Glaser
  • Mark D. Lister
  • Richard J. Ulevitch
  • Edward A. Dennis
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 275)


The inflammatory response involves many different types of tissues and cells; a common modulator produced by many of these cells is the eicosanoids. The eicosanoids (prostaglandins, thromboxanes, leukotrienes. hydroxyeicosatetraenoic acids, lipoxins. etc.) are prominent mediators in the development of inflammatory reactions and have, therefore, been a target for therapeutic regulation. More precisely, the actual target has been the enzymes which control the first step of their biosynthesis from arachidonic acid, the cyclooxygenase and the lipoxygenase.


Arachidonic Acid Arachidonic Acid Release Eicosanoid Production Fatty Acid Analog Eicosanoid Biosynthesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dennis. E. A., The Regulation of Eicosanoid Production: Role of Phospholipases and Inhibitors. Bio/Technology 5:1294 (1987).CrossRefGoogle Scholar
  2. 2.
    Koren. H.S., Handwerger. B.S., and Wunderlich. J.R., Identification of macrophage-like characteristics in a cultured murine tumor line., J. Immunol. 114:894 (1975).PubMedGoogle Scholar
  3. 3.
    Ross. M. I., Deems. R. A., Jesaitis. A. J., Dennis. E. A., and Ulevitch. R. J., Phospholipase Activities of the P388D1 Macrophage-Like Cell Line. Arch. Biochem. Biophys. 238:247 (1985).PubMedCrossRefGoogle Scholar
  4. 4.
    Ulevitch. R. J., Sano. M. Watanabe. Y., Lister. M. D., Deems. R. A., and Dennis. E. A., Solubilization and Characterization of a Membrane-Bound Phospholipase A2 from the P388D1 Macrophage-Like Cell Line. J. Biol. Chem. 263:3079 (1988).PubMedGoogle Scholar
  5. 5.
    Lister. M. D., Deems. R. A., Watanabe. Y., Ulevitch. R. J. and Dennis. E. A., Kinetic Analysis of the Ca2+; Dependent. Membrane-Bound. Macrophage Phospholipase A2 and the Effects of Arachidonic Acid. J. Biol. Chem. 263:7506 (1988).PubMedGoogle Scholar
  6. 6.
    Zhang. Y., and Dennis. E. A., Purification and Characterization of Lysophospholipase from P388D1 Macrophage-Like Cell Line. J. Biol. Chem. 263:9965 (1988).PubMedGoogle Scholar
  7. 7.
    Lister. M. D., Glaser. K. B., Ulevitch. R. J., and Dennis. E.A., Inhibition Studies on the Membrane-Associated Phospholipase A2 in vitro and Prostaglandin E2 Production in vivo of the Macrophage-Like P388D1 Cells: Effects of Manoalide. 7.7-Dimethyl-5.8-eicosadienoic Acid. and p-Bromophenacyl Bromide. J. Biol. Chem. 264:8520 (1989).PubMedGoogle Scholar
  8. 8.
    Leslie. C.C., Voelker. D.R., Channon. J.Y., Wall. M.M., and Zelarney. P.T., Properties and purification of an arachidonyl-hydrolyzing phospholipase A2 from a macrophage cell line. RAW 264.7., Biochim. Biophys. Acta. 963:476 (1988).PubMedCrossRefGoogle Scholar
  9. 9.
    Wijkander. J., and Sundler, R., A phospholipase A2 hydrolyzing arachidonoyl-phospholipids in mouse peritoneal macrophages., FEBS 244:51 (1989).CrossRefGoogle Scholar
  10. 10.
    Okazaki. T., Okita. J.R., MacDonald. P.C., and Johnston. J.M., Initiation of parturition: X. Substrate specificity of phospholipase A2 in human fetal membranes., Amer. J. Obstet Gynecol. 130.432 (1978).Google Scholar
  11. 11.
    Loeb. L.A., and Gross. R.W., Identification and purification of sheep platelet phospholipase A2 isoforms., J. Biol. Chem. 261:10467 (1986).PubMedGoogle Scholar
  12. 12.
    Ban. C., Billah. M.M., Truang. T., and Johnston, J.M., Metabolism of platelet-activating factor (l-0-alkyl-2-acetyl-s/f-glycero-3-phosphocholine) in human fetal membranes and decidua vera., Arch. Biochem. Biophys. 246:9 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    Chilton. F.H., and Connell. J.R., 1-ether-linked phosphoglycerides: major endogenous sources of arachidonate in the human neutrophil., J. Biol. Chem. 263:5260 (1988).PubMedGoogle Scholar
  14. 14.
    Blank. M.L., Smith. Z.L., Lee. Y.J., and Snyder, F., Effects of eicosapentaenoic and docosahexaenoic acid supplements on phospholipid composition and plasmalogen biosynthesis in P388D1 cells., Arch. Biochem. Biophys. 269.603 (1989).PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen. N., Weber. G., Banner. B.L., Welton. A.F., Hope. W.C., Crowley. H., Anderson. W.A., Simko. B.A., O’Donnell. M., Coffey. J.W., Fiedler-Nagy. C., and Batula-Bernardo, C., Analogs of arachidonic acid methylated at C-7 and C-10 as inhibitors of leukotriene biosynthesis., Prostaglandins 27:553 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    de Silva. E.D., and Scheuer. P.J., Manoalide. an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis., Tetrahedron Lett. 21:1611 (1980).CrossRefGoogle Scholar
  17. 17.
    Lombardo. D., and Dennis. E. A., Cobra Venom Phospholipase A2 Inhibition by Manoalide: A Novel Type of Phospholipase Inhibitor. J. Biol. Chem. 260.7234 (1985).PubMedGoogle Scholar
  18. 18.
    Glaser. K.B., and Jacobs, R.S., Molecular pharmacology of manoalide: inactivation of bee venom phospholipase A2., Biochem. Pharmacol. 35:449 (1986).PubMedCrossRefGoogle Scholar
  19. 19.
    Glaser. K.B., Vedvick. T.S., and Jacobs. R.S., Inactivation of phospholipase A2 by manoalide: localization of the manoalide binding site on bee venom phospholipase A2., Biochem. Pharmacol. 37:3639 (1989).CrossRefGoogle Scholar
  20. 20.
    Glaser. K.B., and Jacobs. R.S., Inactivation of bee venom phospholipase A2 by manoalide: a model based on the reactivity of manoalide with amino acids and peptide sequences., Biochem. Pharmacol. 36:2079 (1988).CrossRefGoogle Scholar
  21. 21.
    Reynolds, L. J., Morgan. B. P., Hite. G. A., Mihelich. E. D., and Dennis. E. A., Phospholipase A2 Inhibition and Modification by Manoalogue. J. Am. Chem. Soc. 110.5172 (1988).CrossRefGoogle Scholar
  22. 22.
    Nitta. T., and Suzuki. T., Fc γ2b receptor-mediated prostaglandin synthesis by a murine macrophage cell line (P388D1)., J. Immunol. 120:2527 (1982).Google Scholar
  23. 23.
    Aussel. C. and Fehlman. M., α-fetoprotein stimulates leukotriene synthesis in P388D1 macrophages., Cell. Immunol. 101:415 (1986).PubMedCrossRefGoogle Scholar
  24. 24.
    McGuire. J.C., Richard. K.A., Sun. F.F., and Tracey, D.E., Production of prostaglandin D2 by murine macrophage cell lines., Prostaglandins 30:949 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    Tripp. C.S., Leahy. K.M., and Neeleman. P., Thromboxane synthase is preferentially conserved in activated mouse peritoneal macrophages., J. Clin. Invest 76:898 (1985).PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Mayer. A.M.S., Glaser. K.B., and Jacobs. R.S., Regulation of eicosanoid biosynthesis in vitro and in vivo by the marine natural product manoalide: a potent inactivator of venom phospholipases., J. Pharm. Exp. Ther. 244:871 (1988).Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Keith B. Glaser
    • 1
  • Mark D. Lister
    • 1
  • Richard J. Ulevitch
    • 2
  • Edward A. Dennis
    • 1
  1. 1.Department of ChemistryUniversity of California at San DiegoLa JollaUSA
  2. 2.Department of ImmunologyScripps Clinic and Research InstituteLa JollaUSA

Personalised recommendations