LTB4 and PAF in the Cytokine Network

  • Marek Rola-Pleszczynski
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 314)


In most instances when the host is asked to mount a specific immune response, the initial event or the subsequent response, or both, are associated with non-specific inflammation. In recent years, with the identification of numerous molecular and cellular components of the inflammatory response, investigators have initiated studies of potential interactions between the latter and the protagonists of more specific immunological reactions. In particular, soluble mediators of inflammation, produced by phagocytes, endothelial cells or nerves have been studied in regard to their possible modulation of lymphocyte and monocyte-macrophage functions. In the present chapter, we will focus on a group of lipid molecules, the leukotrienes (LTs) and platelet-activating factor (PAF), and their potential role in modulation of the immune response at the cytokine level.


Platelet Activate Factor Human Monocyte TNFa Production Large Granular Lymphocyte Tumor Necrosis Factor Production 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    P. Borgeat, and B. Samuelsson, Metabolism of arachidonic acid in polymorphonuclear leukocytes: unstable intermediate in formation of dihydro acids. Proc, Natl Acad. Sri, V.SA 76: 3213(1979).CrossRefGoogle Scholar
  2. 2.
    P. Sirois, and P. Borgeat, Leukotrienes: a new approach to the biochemistry of hypersensitivity. Surv. Immunol. Res. 1: 279 (1982).PubMedGoogle Scholar
  3. 3.
    P. Borgeat, and B. Samuelsson, Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes: formation of a novel dihydro-eicosa-tetraenoic acid. J. Biol. Chem. 254: 2643 (1979).PubMedGoogle Scholar
  4. 4.
    A.W. Ford-Hutchinson, M.A. Bray, M.V. Doig, M.E. Shipley, and M.J.H. Smith, Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leucocytes. Nature 286: 264 (1980).PubMedCrossRefGoogle Scholar
  5. 5.
    J. Palmblad, C.L. Malmsten, A.M. Uden, K.O. Radmar, L. Engstedt, and B. Samuelsson, Leukotriene B4 is a potent stereospecific stimulator of neutrophil Chemotaxis and adherence. Blood 58: 658 (1981).PubMedGoogle Scholar
  6. 6.
    H.J. Showell, P.H. Naccache, P. Borgeat, S. Picard, P. Valerand, E.L. Becker, and R.I. Sha’afi, Characterization of the secretory activity of LTB4 toward rabbit neutrophils. J. Immunol. 128: 811 (1982).PubMedGoogle Scholar
  7. 7.
    D.A. Bass, M.J. Thomas, E.J. Goetzl, E.R. DeChatelet, and C.E. McCall, Lipoxygenase-derived products of arachidonic acid mediate stimulation of hexose uptake in human polymorphonuclear leukocytes. Biochem. Biophys. Res. Commun. 100: 1 (1981).PubMedCrossRefGoogle Scholar
  8. 8.
    M.A. Bray, A.W. Ford-Hutchinson, and M.J.H. Smith, Leukotriene B4: an inflammatory mediator in vivo. Prostaglandins 22: 213 (1981).PubMedCrossRefGoogle Scholar
  9. 9.
    T.F.P. Molski, P.H. Naccache, P. Borgeat, and R.I. Sha’afi, Similarities in the mechanisms by which formylmethionyl-leucyl-phenylalanine, arachidonic acid and leukotriene B4 increase calcium and sodium influxes in rabbit neutrophils. Biochem. Biophys. Res. Commun. 103: 227 (1981).PubMedCrossRefGoogle Scholar
  10. 10.
    D.P. Lew, J.-M. Dayer, C.B. Wollheim, and T. Pozzan, Effect of leukotriene B4 and arachidonic acid on cytosolic-free calcium in human neutrophils. FEBS Lett. 166: 44 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    D.W. Goldman, L.A. Gifford, D.M. Olson, and E.J. Goetzl, Transduction by leukotriene B4 receptors of increases in cytosolic calcium in human polymorphonuclear leukocytes. J. Immunol. 135: 525(1985).PubMedGoogle Scholar
  12. 12.
    T. Andersson, W. Schlegel, A. Monod, K.-H. Krause, O. Stendahl, and D.P. Lew, Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1, 4, 5-trisphosphate. Biochem. J., 240: 333 (1986).PubMedGoogle Scholar
  13. 13.
    S. Mong, G. Chi-Rosso, J. Miller, K. Hoffman, K.A. Raggaitis, P. Bender, and S.T. Crooke, Leukotriene B4 induces formation of inositol phosphates in rat peritoneal polymorphonuclear leukocytes. Mol. Pharmacol. 30: 235 (1986).PubMedGoogle Scholar
  14. 14.
    A.O. Fels, N.A. Pawlowski, E.B. Cramer, T.K. King, A.Z. Cohen, and W.A. Scott, Human alveolar macrophages produce leukotriene B4. Proc. Natl. Acad. Sci. USA 79: 7866 (1982).PubMedCrossRefGoogle Scholar
  15. 15.
    P.A.J. Hewricks, M.E. VanDertol, F. Engels, F.P. Nijkamp and J. Verhoef, Human polymorphonuclear leukocytes release leukotriene B4 during phagocytosis of staphylococus aureus. Inflammation 10: 37 (1986).CrossRefGoogle Scholar
  16. 16.
    N.R. Ferreri, W.C. Howland and H.L. Spiegelberg, Release of leukotrienes C4 and B4 and prostaglandin E2 from human monocytes stimulated with aggregated IgG, IgA and IgE. J. Immunol. 136: 4188 (1986).PubMedGoogle Scholar
  17. 17.
    Dubois, C, Bissonnette, E., Rola-Pleszczynski, M.: Asbestos fibers and silica particles stimulate rat alveolar macrophages to release TNF; autoregulatory role of leukotriene B4. Am. Rev. Resp. Dis., 139: 1257–1264 (1989).PubMedGoogle Scholar
  18. 18.
    J. Maclouf, B. Fruteau de Laclos, and P. Borgeat, Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid. Proc. Natl. Acad. Sci. USA. 79: 6042 (1982).PubMedCrossRefGoogle Scholar
  19. 19.
    F.H. Chilton, J.T. O’Flaherty, C.E. Walsh, M.J. Thomas, R.L. Wykle, L.R. DeChatelet, and B.M. Waite, Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by l-0-alkyl-2-0-acetyl-SN-glycero-3-phosphocholine. J. Biol. Chem. 257: 5402 (1982).PubMedGoogle Scholar
  20. 20.
    A.H. Lin, D.R. Morton, and R.R. Gorman, Acetyl glyceryl ether phosphorylcholine stimulates leukotriene B4 synthesis in human polymorphonuclear leukocytes. J. Clin. Invest., 70: 1058 (1982).PubMedCrossRefGoogle Scholar
  21. 21.
    M.E. Goldyne, G.F. Burrish, P. Poubelle, and P. Borgeat, Arachidonic acid metabolism among human mononuclear leukocytes. Lipoxygenase related pathways. J. Biol. Chem. 259: 8815 (1984).PubMedGoogle Scholar
  22. 22.
    P. Poubelle, P. Borgeat, and M. Rola-Pleszczynski, Assessment of leukotriene B4 synthesis in human lymphocytes using high performance liquid chromatography and radioimmunoassay methods. J. Immunol. 139: 1273 (1987).PubMedGoogle Scholar
  23. 23.
    M.E. Goldyne, and L. Rea, Stimulated T cell and natural killer (NK) cell lines fail to synthesize leukotriene B4. Prostaglandins 34: 783 (1987).PubMedCrossRefGoogle Scholar
  24. 24.
    E.J. Goetzl, Selective feed-back inhibition of the 5-lipoxygenation of arachidonic acid in human T-lymphocytes. Biochem. Biophys. Res. Commun., 1901: 344 (1981).CrossRefGoogle Scholar
  25. 25.
    D. Atluru, E.A. Lianos, J.S. Goodwin, Arachidonic acid inhibits 5-lipoxygenase in human T cells. Biochem. Biophys. Res. Commun. 135: 670 (1986).PubMedCrossRefGoogle Scholar
  26. 26.
    B. Odlander, P.-J. Jakobsson, A. Rosen, and H.-E. Claesson, Human B and T lymphocytes convert leukotriene A4 into leukotriene B4. Biochem. Biophys. Res. Commun. 153: 203 (1988).PubMedCrossRefGoogle Scholar
  27. 27.
    J.L. Ambrus, C.H. Jurgensen, N.L. Witzel, R.A. Lewis, J.L. Butler, and A.S. Fauci, Leukotriene C4 produced by a human T-T hybridoma suppresses Ig production by human lymphocytes. J. Immunol. 140: 2382 (1988).PubMedGoogle Scholar
  28. 28.
    E.M. Davidson, S.A. Rae, and M.J.H. Smith, Leukotriene B4 in synovial fluid. J. Pharm. Pharmacol. 34: 410 (1982).PubMedCrossRefGoogle Scholar
  29. 29.
    S.D. Brain, R.D.R. Camp, P.M. Dowd, A.K. Black, P.M. Woolard, A.I. Mallet, and M.W. Greaves, Psoriasis and leukotriene B4. Lancet 2: 762 (1982).PubMedCrossRefGoogle Scholar
  30. 30.
    Y. Kikawa, Y. Shigematsu, and M. Sudo, Leukotriene B4 and 20-OH-LTB4 in purulent peritoneal exudates demonstrated by GC-MS. Prostagl. Leukotr. Med. 23: 85 (1986).CrossRefGoogle Scholar
  31. 31.
    P. Sharon, and W.F. Stenson, Production of leukotrienes by colonic mucosa from patients with inflammatory bowel disease. Gastroenterol 84: 1306 (1983).Google Scholar
  32. 32.
    R.D. Zipser, C.C. Nast, M. Lee, H.W. Kao, and R. Duke, In vivo production of leukotriene B4 and leukotriene C4 in rabbit colitis. Gastroenterol. 92: 33 (1987).Google Scholar
  33. 33.
    F.H. Chilton, J.M. Ellis, S.C. Olson, and R.L. Wykle. l-0-alkyl-2-arachidonyl-sn-glycero-3-phosphocholine. A common source of platelet-activating factor and arachidonate in human polymorphonuclear leukocytes. J. Biol. Chem. 259: 12014 (1984).PubMedGoogle Scholar
  34. 34.
    P. Braquet, L. Touqui, T.Y. Shen, and B.B. Vargaftig. Perspectives in platelet activating factor research. Pharmacol. Review 39: 97 (1987).Google Scholar
  35. 35.
    E. Jouvin-Marche, E. Ninio, G. Beauvain, M. Tence, P. Niaudet and J. Benveniste. Biosynthesis of PAF-acether (platelet-activating factor). VII. Precursors of PAF-acether and acetyl-transferase activity in human leukocytes. J. Immunol. 133: 892 (1984).PubMedGoogle Scholar
  36. 36.
    F. Bussolino, R. Foa, F. Malavasi, M.L. Ferrando, and G. Camussi. Release of platelet-activating factor (PAF)-like material from human lymphoid cell lines. Exp. Haematol. 12: 688 (1984).Google Scholar
  37. 37.
    F. Malavasi, C. Tetta, A. Funaro, G. Bellone, E. Ferrero, and F. Caligaris-Cappio. Fc receptor triggering induces expression of surface activation antigens and release of platelet-activating factor in large granular lymphocytes. Proc. Natl. Acad. Sci. (USA), 83: 2443(1986).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Rola-Pleszczynski, Immunoregulation by leukotrienes and other lipoxygenase metabolites. Immunol. Today 6: 302 (1985).CrossRefGoogle Scholar
  39. 39.
    P. Braquet, M. Rola-Pleszczynski. Platelet-activating factor and cellular immune responses. Immunol. Today. 8: 345 (1987).CrossRefGoogle Scholar
  40. 40.
    C.A. Dinarello, I. Bishai, L.J. Rosenwasser and F. Coceani. The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin 1). Int. J. Immunopharmacol. 1: 43 (1984).CrossRefGoogle Scholar
  41. 41.
    M. Rola-Pleszczynski and I. Lemaire. Leukotrienes augment interleukin 1 production by human monocytes. J. Immunol. 135: 3958(1985).PubMedGoogle Scholar
  42. 42.
    M. Rola-Pleszczynski, L. Bouvrette, D. Gingras and M. Girard. Identification of interferon-γ as the lymphokine that mediates leukotriene B4-induced immunoregulation. J. Immunol. 139: 513 (1987).PubMedGoogle Scholar
  43. 43.
    P. Poubelle, J. Stankova, J. Grassi, M. Rola-Pleszczynski. Leukotriene B4 up-regulates IL-6 rather than IL-1 synthesis in human monocytes. Agents and Actions, in press, 1991.Google Scholar
  44. 44.
    L. Gagnon, L. Fillion, C. Dubois, and M. Rola-Pleszczynski. Leukotrienes and macrophage activation: augmented cytotoxic activity and enhanced interleukin 1, tumor necrosis factor and hydrogen peroxide production. Agents and Actions, 26: 141 (1989).PubMedCrossRefGoogle Scholar
  45. 45.
    L. Gagnon, L.G. Filion, M. Rola-Pleszczynski. Enhanced production of tumor necrosis factor (TNF)-α by human monocytes exposed to leukotriene B4. Int. J. Immunopathol. Pharmacol. 2: 155 (1989).Google Scholar
  46. 46.
    M. Rola-Pleszczynski, P.-A. Chavaillaz, and I. Lemaire. Stimulation of interleukin 2 and interferon-γ production by leukotriene B4 in human lymphocyte cultures. Prostagl. Leukotr. Med. 23: 207 (1986).CrossRefGoogle Scholar
  47. 47.
    M. Rola-Pleszczynski, L. Gagnon, and P.-A. Chavaillaz. Immune regulation by leukotriene B4. in: “Biology of the leukotrienes.”, R. Levi and R.D. Krell, eds., Ann. N.Y. Acad. Sci., 524: 218 (1988).Google Scholar
  48. 48.
    H.M. Johnson, and B.A. Torres. Leukotrienes, positive signals for regulation of interferon-production. J. Immunol., 132: 413 (1984).PubMedGoogle Scholar
  49. 49.
    W.L. Farrar, and J.L. Humes. The role of arachidonic acid metabolism in the activities of interleukin 1 and 2. J. Immunol. 135: 1153 (1985).PubMedGoogle Scholar
  50. 50.
    H.-P. Hartung. Acetyl glyceryl ether phosphoryl-choline (platelet-activating factor) mediates heightened metabolic activity in macrophages. Studies on PGE1, TXA2 and O2 production, spreading and the influence of calmodulin inhibitor W-7. FEBS Lett. 160: 209 (1983).PubMedCrossRefGoogle Scholar
  51. 51.
    Y.-S. Ho, W.M.F. Lee, and R. Snyderman. Chemoattractant-induced activation of c-fos gene expression in human monocytes. J. Exp. Med. 165: 1524 (1987).PubMedCrossRefGoogle Scholar
  52. 52.
    H. Homma, D.J. Hanahan. Attenuation of platelet-activating factor (PAF)-induced stimulation of rabbit platelet GTPase by phorbol ester, dibutyryl cAMP, and desensitisation: concomitant effects on PAF receptor binding characteristics. Arch. Biochem. Biophys. 262: 32(1988).PubMedCrossRefGoogle Scholar
  53. 53.
    M. Bachelet, M.J.P. Adolfs, J. Masliah, G. Bereziat, B.B. Vargaftig, and I.L. Bonta. Interaction between PAF-acether and drugs that stimulate cyclic AMP in guinea-pig alveolar macrophages. Eur. J. Pharmacol. 149: 73 (1988).PubMedCrossRefGoogle Scholar
  54. 54.
    G. Barzaghi, and S. Mong. Platelet-activating factor (PAF) stimulates a phospholipase C(PLC) in differentiated human monocytic leukemia (U-937) cells, resulted in phosphoinositide (PI) hydrolysis and intracellular calcium mobilization. Prostaglandins 35: 819 (1988).CrossRefGoogle Scholar
  55. 55.
    S. Hopple, R. Meurer, J. Westwick, and D.E. MacIntyre. PAF-induced Ca2+ flux and formation of inositol tris-and tetrakis-phosphates in U937 cells. FASEB J 2: A415 (1988).Google Scholar
  56. 56.
    V. Prpic, R.J. Uhing, J.E. Weiel, L. Jakoi, G. Gawdi, B. Herman, and D.O. Adams. Biochemical and functional responses stimulated by platelet-activating factor in murine peritoneal macrophages. J. Cell. Biol. 107: 363 (1988).PubMedCrossRefGoogle Scholar
  57. 57.
    F. Bussolino, F. Turrini, E. Fischer, D. Alessi, M.D. Kazatchkine, and P. Arese. PAF enhances erythrophagocytic activity of human monocytes by the protein kinase C dependent phosphorylation of C36 receptor (CR1). Role of PAF receptor antagonists. Prostaglandins 35: 803(1988).CrossRefGoogle Scholar
  58. 58.
    B. Pignol, S. Hénane, J.-M. Mencia-Huerta, M. Rola-Pleszczynski, and P. Braquet. Effect of platelet-activating factor (PAF-acether) and its specific receptor antagonist, BN 52021, on interleukin 1 (IL 1) release and synthesis by rat spleen adherent monocytes. Prostaglandins, 33: 931 (1987).PubMedCrossRefGoogle Scholar
  59. 59.
    B. Pignol, S. Hénane, B. Sorlin, B. M. Rola-Pleszczynski, J.-M. Mencia-Huerta, P Braquet. Effect of long-term treatment with platelet-activating factor on IL 1 and IL 2 production by rat spleen cells. J. Immunol. 145: 980 (1990).PubMedGoogle Scholar
  60. 60.
    M.L. Barrett, G.P. Lewis, S. Ward, and J. Westwick. Plateletactivating factor induces interleukin 1 production from human adherent macrophages. Br. J. Pharmacol. 90: 113P (1987).Google Scholar
  61. 61.
    P. Salem, S. Derickx, A. Dulioust, E. Vivier Y. Denizot, C. Damais, C. Dinarello, Y. Thomas. Immunoregulatory functions of paf-acether. Enhancement of IL 1 production by muramyl dipeptide-stimulated monocytes. J. Immunol. 144: 1338(1990).PubMedGoogle Scholar
  62. 62.
    P. Poubelle, D. Gingras, C. Demers, C. Dubois, D. Harbour, and M. Rola-Pleszczynski, M. Platelet activating factor (PAF-acether) enhances the concomitant production of tumor necrosis factor alpha and interleukin 1 by subsets of human monocytes. Immunol. in press, 1991.Google Scholar
  63. 63.
    R. Barthelson, F. Valone. Interaction of platelet-activating factor with interferon-γ in the stimulation of interleukin-1 production by human monocytes. J. Allergy Clin. Immunol. 86: 193 (1990).PubMedCrossRefGoogle Scholar
  64. 64.
    F.H. Valone, and L.B. Epstein. Biphasic platelet-activating factor (PAF) synthesis by human monocytes stimulated with interleukin 1 beta (IL Iβ), tumor necrosis factor (TNF) or IFN-γ. J. Immunol. 141: 3945 (1988).PubMedGoogle Scholar
  65. 65.
    G.M. Vercellotti, H.Q Yin, K.S. Gustabson, R.D. Nelson, and H.S. Jacob. Platelet-activating factor primes neutrophils responses to agonists: role in promoting neutrophil-mediated endothelial damage. Blood 71: 1100 (1988).PubMedGoogle Scholar
  66. 66.
    M. Paubert-Braquet, M.-O. Lonchampt, P. Klotz, and J. Guilbaud. Tumor necrosis factor (TNF) primes platelet-activating factor (PAF)-induced superoxide generation by human neutrophils (PMN): consequences in promoting PMN-mediated endothelial cell (EC) damages. Prostaglandins 35: 803 (1988).CrossRefGoogle Scholar
  67. 67.
    G.S. Worthen, J.F. Seccombe, K.L. Clay, L.A. Guthrie, and R.B. Jr Johnston. The priming of neutrophils by lipopolysaccharide for production of intracellular platelet-activating factor. J. Immunol. 140: 3553(1988).PubMedGoogle Scholar
  68. 68.
    M. Rola-Pleszczynski, L. Bouvrette, M. Thivierge, C. Lacasse. Platelet-activating factor enhances interleukin 6 production by monocytes, alveolar macrophages and endothelial cells. FASEB J. 4: A1713 (1990).Google Scholar
  69. 69.
    M. Rola-Pleszczynski, J. Bossé, E. Bissonnette and C. Dubois. PAF-acether enhances the production of tumor necrosis factor by human and rodent lymphocytes and macrophages. Prostaglandins 35: 802 (1988).CrossRefGoogle Scholar
  70. 70.
    C. Dubois, E. Bissonnette, M. Rola-Pleszczynski, M. Platelet-activating factor (PAF) stimulates tumor necrosis factor production by alveolar macrophages: prevention by PAF receptor antagonists and lipoxygenase inhibitors J. Immunol. 143: 964 (1989).PubMedGoogle Scholar
  71. 71.
    Bonavida, Braquet, P. Effect of platelet-activating factor (PAF) on monocyte activation and production of tumor necrosis factor (TNF). Int. Arch. Allergy Appl. Immunol. (1988).Google Scholar
  72. 72.
    M. Rola-Pleszczynski, J. Stankova. Differentiation-dependent modulation of TNF production by PAF in human HL-60 myeloid leukemia cells. Submitted for publication, J. Immunol. (1990).Google Scholar
  73. 73.
    M. Rola-Pleszczynski. Priming of human monocytes with PAF augments their production of tumor necrosis factor. J. Lipid Mediators 2: S77 (1990).Google Scholar
  74. 74.
    J. Bossé, S. Turcotte, and M. Rola-Pleszczynski. Platelet activating factor (PAF) enhances the production of cytotoxic cytokines during natural cell-mediated cytotoxicity. FASEB J. 2: A415 (1988).Google Scholar
  75. 75.
    C. Lacasse, and M. Rola-Plesczcynski. Immune regulation by PAF II. Mediation of suppression by cytokine-stimulated endothelial cells. J. Leuk. Biol., in press,1990.Google Scholar
  76. 76.
    M. Rola-Pleszczynski, B. Pignol, C. Pouliot, and P. Braquet, Inhibition of human lymphocyte proliferation and interleukin 2 production by platelet-activating factor (PAF-acether): Reversal by a specific antagonist: BN52021. Biochem. Biophys. Res. Commun., 142: 754(1987).PubMedCrossRefGoogle Scholar
  77. 77.
    A. Dulioust, V. Duprez, C. Pittou, P. Salem, A. Hemar, J. Benveniste, Y. THomas,. Immunoregulatory functions of PAF-acether. Downregulation of CD4+ T cells high affinity IL 2 receptor expression, J. Immunol. 144: 3123 (1990).PubMedGoogle Scholar
  78. 78.
    M. Rola-Pleszczynski, C. Pouliot, S. Turcotte, B. Pignol, P. Braquet and L. Bouvrette.: Immune regulation by platelet-activating factor. I. Induction of suppressor cell activity in human monocytes and CD8+ T cells and of helper cell activity in CD4+T cells. J. Immunol. 140: 3547 (1988).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Marek Rola-Pleszczynski
    • 1
  1. 1.Immunology Division, Department of Pediatrics, Faculty of MedicineUniversity of SherbrookeSherbrookeCanada

Personalised recommendations