Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Nonsteroidal antiinflammatory drugs exert differential effects on neutrophil function and plasma membrane viscosity

Studies in human neutrophils and liposomes


Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit neutrophil functions via mechanisms separate from their capacity to inhibit prostaglandin synthesis. We have studied discrete events in the process of signal transduction: NSAIDs but not a related analgesic drug (acetaminophen), inhibited aggregation in response to the chemoattractants f-Met-Leu-Phe (FMLP), leukotriene B4, and C5a. NSAIDs, but not acetaminophen, inhibited binding of radiolabeled FMLP to purified neutrophil membranes. Gpp(NH)p, a GTPase insensitive analog of GTP, also inhibited the binding of FMLP but, paradoxically, enhanced superoxide anion generation and lysozyme release. The inhibition of ligand binding by NSAIDs did not correlate with their capacity to inhibit FMLP-induced increments in diacylglycerol (DG): piroxicam, but not salicylate effectively inhibited appearance of label ([3H]arachidonate, [14C] glycerol) in DG. Finally, NSAIDs exerted differential effects on the viscosity of neutrophil plasma membranes and multilamellar vesicles (liposomes): membrane viscosity was increased by piroxicam and indomethacin, decreased by salicylate, and unaffected by acetaminophen. Thus, the different effects of NSAIDs on discrete pathways are not due to their shared capacity to reduce ligand binding but rather to a capacity to uncouple postreceptor signaling events that depend upon the state of membrane fluidity.

This is a preview of subscription content, log in to check access.


  1. 1.

    Vane, J. R. 1971. Inhibition of prostaglandin synthesis as a mechanism of action for aspirinlike drugs.Nature (London) New Biol. 231:232–235.

  2. 2.

    Abramson, S. B., H. Korchak, R. Ludewig, H. Edelson, K. Haines, R. Herman, L. Rider, S. Kimmel, andG. Weissmann. 1985. Modes of action of aspirin-like drugs.Proc. Natl. Acad. Sci. U.S.A. 82:7227–7231.

  3. 3.

    Walker, J., M. Smith, andA. W. Ford-Hutchinson. 1976. Anti-inflammatory drugs, prostaglandins and leukocyte migration.Agents Actions 6:602–606.

  4. 4.

    Perianin, A., M. Torres, M. Labro, andJ. Hakin. 1983. The different inhibitory effects of phenylbutazone on soluble and particle stimulation of human neutrophil oxidative burst.Biochem. Pharmacol. 32:2819–2822.

  5. 5.

    Perianin, A., M. Roch-Arveiller, J. P. Giround, andJ. Hakin. 1988. In vivo interaction of non-steroidal antiinflammatory drugs on the locomotion of neutrophils elicited by acute nonspecific inflammations in the rat-effect on indomethacin, ibuprofen and flurbiprofen.Biochem. Pharmacol. 33:2239–2243.

  6. 6.

    Hopkins, N. K., A. Lin, andR. Groman. 1983. Evidence for mediation of acyl-glycerol ether phsophorylcholine stimulation of adenosine 5'-(cyclic) monophophate levels in human polymorphonuclear leukocytes by leukotriene B4.Biochim. Biophys. Acta 763:276–283.

  7. 7.

    Ford-Hutchinson, A. W.. 1983. Neutrophil aggregating properties of PAF-acether and leukotriene B4.Int. J. Immunopharmacol. 13(5):17–21.

  8. 8.

    Simchowitz, L., J. Mehta, andI. Spilber T. 1979. Chemotactic factor-induced generation of superoxide radicals by human neutrophils.Arthritis Rheum. 22:755–763.

  9. 9.

    Kaplan, H., H. Edelson, H. Korchak, W. Given, S. Abramson, andG. Weissmann. 1984. Effects of non-steroidal anti-inflammatory agents on human neutrophil functions in vitro and in vivo.Biochem. Pharmacol. 33:371–378.

  10. 10.

    Perez, H. D., F. Elfman, andS. Marder. 1987. Meclofenamate sodium monhydrate inhibits chemotactic factor-induced human polymorphonuclear leukocyte function: A possible explanation for its antiinflammatory effect.Arthritis Rheum. 30:1023–1031.

  11. 11.

    Bomalaski, J. S., R. Hirata, andM. Clark. 1986. Aspirin inhibits phospholipase C.Biochem. Biophys. Res. Commun. 139:115–121.

  12. 12.

    Minta, J., andM. J. Williams 1985. Some nonsteroidal antiinflammatory drugs inhibit the generation of superoxide anion by activated Polymorphs by blocking ligand-receptor interaction.J. Rheum. 12:751–757.

  13. 13.

    Bittman, R., andL. Blau. 1972. The phospholipid-cholesterol interaction. Kinetics of water permeability in liposomes.Biochemistry 11:4831–4839.

  14. 14.

    Goldstein, I. M., M. Brai, A. G. Osler, andG. Weissmann. 1973. Lysosomal enzyme release from the human leukocyte: Mediation by the alternate pathway of complement activation.J. Immunol. 111:33–37.

  15. 15.

    Goldstein, I. M., M. Cerqueira, S. Lind, andH. B. Kaplan. 1977. Evidence that the superoxide-generating system of human leukocytes is associated with the cell surface.J. Clin. Invest. 59:249–254.

  16. 16.

    Buyon, J. P., S. B. Abramson, M. R. Philips, S. G. Slade, G. D. Ross, G. Weissmann, andR. J. Winchester. 1988. Dissociation between increased surface expression of Gp165/ 95 and homotypic neutrophil aggregation.J. Immunol. 140:3156–3160.

  17. 17.

    Boyum, A.. 1986. Isolation of mononuclear cells and granulocytes from human blood.Scand. J. Clin. Lab. Invest. Suppl. 97:77–89.

  18. 18.

    Koo, C., R. J. Lefkowitz, andR. Snyderman. 1983. Guanine nucleotides modulate the binding affinity of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes.J. Clin. Invest. 72:748–753.

  19. 19.

    Lowry, O. H., N. J. Rosebrough, A. L. Farr, andR. J. Randall. 1951. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193:265–275.

  20. 20.

    Reibman, J., H. M. Korchak, L. B. Vosshall, K. A. Haines, A. M. Rich, andG. Weissmann. 1988. Changes in diacylglycerol labeling, cell shape and protein phosphorylation distinguish “triggering” from “activation” of human neutrophils.J. Biol. Chem. 263:6322–6328.

  21. 21.

    Bligh, E.G., andW. J. Dyer. 1959. A rapid method of total lipid extraction and purification.Can. J. Biochem. Physiol. 37:911–917.

  22. 22.

    Valentino, M., M. Governa, R. Fiorini, andG. Curatola. 1986. Changes of membrane fluidity in chemotactic peptide stimulated polymorphonuclear leukocytes.Biochem. Biophys. Res. Commun. 141:1151–1156.

  23. 23.

    Prendergast, F. G., R. P. Haugland, andP. J. Callahan. 1981. l-[4-(trimethylamine)phenyl]-6-phenylhexa-a,3,5,-triene: Synthesis, fluorescence properties, and scuse as a fluorescence probe of lipid bilayers.Biochemistry 20:7333–7338.

  24. 24.

    Yuli, I., A. Tomonaga, andR. Snyderman. 1982. Chemoattractant receptor functions in human polymorphonuclear leukocytes are divergently altered by membrane fluidizers.Proc. Natl. Acad. Sci. U.S.A. 79:5906–5910.

  25. 25.

    Korchak, H. M., K. Vienne, L. E. Rutherford, C. Wilkenfeld, M. Finkelstein, andG. Weissmann. 1984. Stimulus response coupling in the human neutrophil. II. Temporal analysis of changes in cytosolic calcium and calcium efflux.J. Biol. Chem. 259:4076–4082.

  26. 26.

    Gabig, T. G., D. English, L. P. Akard, andSchall. 1987. Regulation of neutrophil NADPH oxidase activation in a cell-free system by guanine and fluoride.J. Biol. Chem. 262:1685–1690.

  27. 27.

    Kanaho, Y., Moss, andM. Vanghen. 1985. Mechanism of inhibition of transducin GTPase activity by fluoride and aluminum.J. Biol. Chem. 260:11493–11497.

  28. 28.

    Ross, G. D., andM. E. Medof. 1985. Membrane complement receptors specific for bound fragments of C3.Adv. Immunol. 37:217–267.

  29. 29.

    Berger, M., J. O'Shea, A. S. Cross, T. M. Folk, T. Chused, E. Brown, andM. Frank. 1984. Human neutrophils increase expression of C3bi as well as C3b receptors upon activation.J. Clin. Invest. 74:1566–1571.

  30. 30.

    Schwartz, R., H. D. Ochs, P. G. Beatty, andJ. M. Harlin. 1985. A monoclonal antibody defined membrane antigen complex is required for neutrophil-neutrophil aggregation.Blood 65:1553–1556.

  31. 31.

    Wallis, W. J., D. D. Hiekstein, B. R. Schwartz, C. H. June, H. D. Ochs, P. G. Beatty, S. J. Klebanoff, andJ. M. Harlan. 1986. Monoclonal antibody-defined functional epitopes on the adhesion-promoting glycoprotein complex (CDW 18) of human blood neutrophils.Blood 67:1007–1013.

  32. 32.

    Goodman, L., andGilman. 1980. The Pharmacological Basis of Therapeutics, 6th ed. Macmillian, New York. 701–705.

  33. 33.

    Van Epps, E., S. Greiwe, J. Potter, andJ. Goodwin. 1986. Alterations in neutrophil superoxide production following piroxicam therapy in patients with rheumatiod arthritis.Inflammation 11:59–72.

  34. 34.

    Biemond, P., A. G. Swaak, J. A. Penders, C. M. Beindroff, andJ. F. Koster. 1986. Superoxide production by polymorphonuclear leucocytes in rheumatiod arthritis and osteoarthritis: In vivo inhibition by the antirheumatic drug piroxicam due to interference with the activation of the NADPH-oxidase.Ann. Rheum. Dis. 45:249–255.

  35. 35.

    Montecucco, C., A.Mazzone, D.Pasotti, R.Carorali, M.Longhi, D.Casilli, G.RiceVuti, andFratino. 1988. Effect of piroxicam therapy on granulocyte function and granulocyte elastase concentration in peripheral blood and synovial fluid of rheumatoid arthritis patients.Inflammation.

  36. 36.

    Palmoski, M. J., andK. D. Brandt. 1984. Effects of lasicylate and indomethacin on glycosaminoglycam and prostaglandin E2 synthesis in intact canine knee cartilage ex vivo.Arthritis Rheum. 27:398–403.

  37. 37.

    Palmoski, M. J., andK. D. Brandt. 1985. Correction of data on salicylate and indomethacim concentrations in cartilage.Arthritis Rheum. 28:237.

  38. 38.

    Smith, R. J., andS. Iden. 1980. Pharmacological modulation of chemotactic factor-elicited release of granule-associated enzymes from human neutrophils.Biochem. Pharmacol. 29:2389–2395.

  39. 39.

    Lombardino, J., I. Otterness, andE. Wiseman. 1975. Acidic antiinflammatory agents.Arzneim-Forsch 25:1629–1634.

  40. 40.

    Smith, M., andR. Dawkins. 1971. Salicylate and enzymes.J. Pharm. Pharmacol. 23:729–744.

  41. 41.

    Philips, M. R., J. P. Buyon, R. Winchester, G. Weissmann, andS. B. Abramson. 1988. Up-regulation of the iC3b receptor (CR3) is neither necessary nor sufficient to promote neutrophil aggregation.J. Clin. Invest. 82:495–501.

  42. 42.

    Stenson, W. F., J. Mehta, andI. Spilberg. 1984. Sulfasalazine inhibition of binding ofn- formyl-methionyl-leucyl-phenylalanine (FMLP) to its receptor on human neutrophils.Biochem. Pharmacol. 33:407–412.

  43. 43.

    Smith, C. D., R. J. Lefkowitz, andR. Snyderman. 1983. Guanine nucleotides modulate the binding affinity of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes.J. Clin. Invest. 72:748–753.

  44. 44.

    Smith, C. D., C. L. Cox, andR. Snyderman. 1980. Receptor coupled activation of phosphoinositide-specific phospholipase C by an N protein.Science 232:97–100.

  45. 45.

    Siegel, M., R. McConnell, andR. Cuatrecasas. 1979. Aspirin-like Drugs interfere with arachidonate metabolism by inhibition of the 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway.Proc. Natl. Acad. Sci. U.S.A. 76:3774–3778.

  46. 46.

    Miyahara, J. T., andR. Karler. 1965. Effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragments.Biochem. J. 97:194–198.

  47. 47.

    Bomalaski, J. S., Alvarez, J. Touchstone, andR. Zurier. 1987. Alteration of uptake and distribution of eicosanoid precursor fatty acids by aspirin.Biochem. Pharmacol. 36:3249–3253.

  48. 48.

    Lucas-Heron, B., andC. Fontenaille. 1979. Urate transport in human red blood cells. Activation by ATP.Biochim. Biophys. Acta 553:284–294.

  49. 49.

    Kim, L. A., J. D. Tuama, Mann, andRoe. 1983. Saturable accumulation of the anioni herbicide 2,4-dichlorophenoxyacetic by rabbit choroid plexus: Early developmental origin and interaction with salicylates.J. Pharmacol. Exp. Ther. 225:699–704.

  50. 50.

    Snow, I. B., andA. R. Mass. 1979. Renal sites of natiuretic and uricosuric activity of ticrynafen in the mongrel dog.Nephron 23:15–20

  51. 51.

    Korchak, H. M., B. A. Eisenstat, J. E. Smolen, L. E. Rutherford, P. B. Dunham, andG. Weissmann. 1982. Stimulus-response coupling in the human neutrophil: The role of anion fluxes in degranulation.J. Biol, Chem. 257:6916–6922.

  52. 52.

    Weissmann, G., L. Azaroff, S. Davidson, andP. Dunham. 1986. Synergy between phorbol esters, l-oleyl-2-acetylglycerol, urushiol and calcium ionophore in eliciting aggregation of marine sponge cells.Proc. Natl. Acad. Sci. U.S.A. 83:2914–2918.

  53. 53.

    Weissmann, G., W. Reisen, S. Davidson, andM. Waite. 1988. Stimulus-response coupling in marine sponge cell aggregation: Lipid metabolism and the function of exogenously added arachidonic and docosahexaenoic acids.Biochim. Biophys. Acta 960:351–364.

Download references

Author information

Additional information

This work was supported by Project 8 of National Institutes of Health grant AR 01431 to S.A. and NIH AM 11949, HL 19721 and Project 7 and Core of AR 01431 to G.W.

With the technical assistance of R. Ludewig, L. Vosshall and S. Yokota.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Abramson, S.B., Cherksey, B., Gude, D. et al. Nonsteroidal antiinflammatory drugs exert differential effects on neutrophil function and plasma membrane viscosity. Inflammation 14, 11–30 (1990).

Download citation


  • Indomethacin
  • Acetaminophen
  • Salicylate
  • Piroxicam
  • Arachidonate