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. 1987 Nov 1;166(5):1390–1404. doi: 10.1084/jem.166.5.1390

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor

PMCID: PMC2189646  PMID: 3119758

Abstract

Murine tumor necrosis factor (mTNF) stimulates production of platelet- activating factor (PAF) by cultured rat peritoneal macrophages in amounts comparable to those formed during treatment with the calcium ionophore A23187 or phagocytosis of zymosan. The cell-associated PAF that was released into the medium was identical to synthetic PAF, as determined with physicochemical, chromatographic, and enzymatic assays. Furthermore, de novo synthesis of PAF by macrophages was demonstrated by the incorporation of radioactive precursors such as [3H]acetyl- coenzyme A or [3H]2-lyso-PAF. Macrophages incubated with mTNF for 4 h synthesized PAF only during the first h of treatment. At this time, the amount of cell-associated PAF was approximately equal to that released into the medium. The cell-associated PAF decreased afterwards, whereas that in the medium did not correspondingly increase, suggesting that some PAF was being degraded. The response of rat macrophages to different doses of mTNF and human TNF (hTNF) was examined. Maximal synthesis of PAF was obtained with 10 ng/ml of mTNF and 50 ng/ml of hTNF. This finding may be explained by a lower affinity of hTNF for TNF receptors of rat cells. The hTNF stimulated production of PAF by human vascular endothelial cells cultured from the umbilical cord vein. The time course of PAF synthesis was slower than that observed with macrophages, with maximal production between 4 and 6 h of treatment. Optimal synthesis of PAF was obtained with 10 ng/ml of hTNF. Only 20- 30% of the PAF synthesized by endothelial cells was released into the medium, even after several hours of incubation. Synthesis of PAF in response to TNF was also detected in rat polymorphonuclear neutrophils, but not in human tumor cells and dermal fibroblasts. Therefore, production of PAF is a specialized response that is transient in macrophages continuously treated with TNF, and that appears to be controlled by unidentified regulatory mechanisms.

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Selected References

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  1. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  2. Benveniste J., Chignard M., Le Couedic J. P., Vargaftig B. B. Biosynthesis of platelet-activating factor (PAF-ACETHER). II. Involvement of phospholipase A2 in the formation of PAF-ACETHER and lyso-PAF-ACETHER from rabbit platelets. Thromb Res. 1982 Mar 1;25(5):375–385. doi: 10.1016/0049-3848(82)90128-1. [DOI] [PubMed] [Google Scholar]
  3. Benveniste J., Henson P. M., Cochrane C. G. Leukocyte-dependent histamine release from rabbit platelets. The role of IgE, basophils, and a platelet-activating factor. J Exp Med. 1972 Dec 1;136(6):1356–1377. doi: 10.1084/jem.136.6.1356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benveniste J., Le Couedic J. P., Polonsky J., Tence M. Structural analysis of purified platelet-activating factor by lipases. Nature. 1977 Sep 8;269(5624):170–171. doi: 10.1038/269170a0. [DOI] [PubMed] [Google Scholar]
  5. Benveniste J., Tencé M., Varenne P., Bidault J., Boullet C., Polonsky J. Semi-synthèse et structure proposée du facteur activant les plaquettes (P.A.F.): PAF-acether, un alkyl ether analogue de la lysophosphatidylcholine. C R Seances Acad Sci D. 1979 Nov 26;289(14):1037–1040. [PubMed] [Google Scholar]
  6. Bessin P., Bonnet J., Apffel D., Soulard C., Desgroux L., Pelas I., Benveniste J. Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs. Eur J Pharmacol. 1983 Jan 21;86(3-4):403–413. doi: 10.1016/0014-2999(83)90190-5. [DOI] [PubMed] [Google Scholar]
  7. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  8. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  9. Bevilacqua M. P., Pober J. S., Majeau G. R., Fiers W., Cotran R. S., Gimbrone M. A., Jr Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4533–4537. doi: 10.1073/pnas.83.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bloom G. D., Fredholm B., Haegermark O. Studies on the time course of histamine release and morphological changes induced by histamine liberators in rat peritoneal mast cells. Acta Physiol Scand. 1967 Dec;71(4):270–282. doi: 10.1111/j.1748-1716.1967.tb03734.x. [DOI] [PubMed] [Google Scholar]
  11. Bussolino F., Breviario F., Aglietta M., Sanavio F., Bosia A., Dejana E. Studies on the mechanism of interleukin 1 stimulation of platelet activating factor synthesis in human endothelial cells in culture. Biochim Biophys Acta. 1987 Jan 19;927(1):43–54. doi: 10.1016/0167-4889(87)90064-4. [DOI] [PubMed] [Google Scholar]
  12. Bussolino F., Gremo F., Tetta C., Pescarmona G. P., Camussi G. Production of platelet-activating factor by chick retina. J Biol Chem. 1986 Dec 15;261(35):16502–16508. [PubMed] [Google Scholar]
  13. Caillard C. G., Mondot S., Zundel J. L., Julou L. Hypotensive activity of PAF-acether in rats. Agents Actions. 1982 Dec;12(5-6):725–730. doi: 10.1007/BF01965093. [DOI] [PubMed] [Google Scholar]
  14. Camussi G., Aglietta M., Coda R., Bussolino F., Piacibello W., Tetta C. Release of platelet-activating factor (PAF) and histamine. II. The cellular origin of human PAF: monocytes, polymorphonuclear neutrophils and basophils. Immunology. 1981 Feb;42(2):191–199. [PMC free article] [PubMed] [Google Scholar]
  15. Camussi G., Aglietta M., Malavasi F., Tetta C., Piacibello W., Sanavio F., Bussolino F. The release of platelet-activating factor from human endothelial cells in culture. J Immunol. 1983 Nov;131(5):2397–2403. [PubMed] [Google Scholar]
  16. Camussi G., Bussolino F., Ghezzo F., Pegoraro L. Release of platelet-activating factor from HL-60 human leukemic cells following macrophage-like differentiation. Blood. 1982 Jan;59(1):16–22. [PubMed] [Google Scholar]
  17. Camussi G., Bussolino F., Tetta C., Piacibello W., Aglietta M. Biosynthesis and release of platelet-activating factor from human monocytes. Int Arch Allergy Appl Immunol. 1983 Mar;70(3):245–251. doi: 10.1159/000233331. [DOI] [PubMed] [Google Scholar]
  18. Camussi G., Pawlowski I., Bussolino F., Caldwell P. R., Brentjens J., Andres G. Release of platelet activating factor in rabbits with antibody-mediated injury of the lung: the role of leukocytes and of pulmonary endothelial cells. J Immunol. 1983 Oct;131(4):1802–1807. [PubMed] [Google Scholar]
  19. Camussi G. Potential role of platelet-activating factor in renal pathophysiology. Kidney Int. 1986 Feb;29(2):469–477. doi: 10.1038/ki.1986.23. [DOI] [PubMed] [Google Scholar]
  20. Camussi G., Tetta C., Deregibus M. C., Bussolino F., Segoloni G., Vercellone A. Platelet-activating factor (PAF) in experimentally-induced rabbit acute serum sickness: role of basophil-derived PAF in immune complex deposition. J Immunol. 1982 Jan;128(1):86–94. [PubMed] [Google Scholar]
  21. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Chang S. W., Feddersen C. O., Henson P. M., Voelkel N. F. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J Clin Invest. 1987 May;79(5):1498–1509. doi: 10.1172/JCI112980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Chap H., Mauco G., Simon M. F., Benveniste J., Douste-Blazy L. Biosynthetic labelling of platelet activating factor from radioactive acetate by stimulated platelets. Nature. 1981 Jan 22;289(5795):312–314. doi: 10.1038/289312a0. [DOI] [PubMed] [Google Scholar]
  24. Chignard M., Le Couedic J. P., Tence M., Vargaftig B. B., Benveniste J. The role of platelet-activating factor in platelet aggregation. Nature. 1979 Jun 28;279(5716):799–800. doi: 10.1038/279799a0. [DOI] [PubMed] [Google Scholar]
  25. Chignard M., Le Couedic J. P., Vargaftig B. B., Benveniste J. Platelet-activating factor (PAF-acether) secretion from platelets: effect of aggregating agents. Br J Haematol. 1980 Nov;46(3):455–464. doi: 10.1111/j.1365-2141.1980.tb05993.x. [DOI] [PubMed] [Google Scholar]
  26. Chilton F. H., O'Flaherty J. T., Ellis J. M., Swendsen C. L., Wykle R. L. Selective acylation of lyso platelet activating factor by arachidonate in human neutrophils. J Biol Chem. 1983 Jun 25;258(12):7268–7271. [PubMed] [Google Scholar]
  27. Clark P. O., Hanahan D. J., Pinckard R. N. Physical and chemical properties of platelet-activating factor obtained from human neutrophils and monocytes and rabbit neutrophils and basophils. Biochim Biophys Acta. 1980 Feb 21;628(1):69–75. doi: 10.1016/0304-4165(80)90352-9. [DOI] [PubMed] [Google Scholar]
  28. Collins T., Lapierre L. A., Fiers W., Strominger J. L., Pober J. S. Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci U S A. 1986 Jan;83(2):446–450. doi: 10.1073/pnas.83.2.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Demopoulos C. A., Pinckard R. N., Hanahan D. J. Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J Biol Chem. 1979 Oct 10;254(19):9355–9358. [PubMed] [Google Scholar]
  30. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Doebber T. W., Wu M. S., Robbins J. C., Choy B. M., Chang M. N., Shen T. Y. Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Commun. 1985 Mar 29;127(3):799–808. doi: 10.1016/s0006-291x(85)80014-0. [DOI] [PubMed] [Google Scholar]
  32. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Halonen M., Palmer J. D., Lohman I. C., McManus L. M., Pinckard R. N. Respiratory and circulatory alterations induced by acetyl glyceryl ether phosphorylcholine, a mediator of IgE anaphylaxis in the rabbit. Am Rev Respir Dis. 1980 Dec;122(6):915–924. doi: 10.1164/arrd.1980.122.6.915. [DOI] [PubMed] [Google Scholar]
  34. Handley D. A., Van Valen R. G., Melden M. K., Flury S., Lee M. L., Saunders R. N. Inhibition and reversal of endotoxin-, aggregated IgG- and paf-induced hypotension in the rat by SRI 63-072, a paf receptor antagonist. Immunopharmacology. 1986 Aug;12(1):11–16. doi: 10.1016/0162-3109(86)90046-9. [DOI] [PubMed] [Google Scholar]
  35. Humphrey D. M., McManus L. M., Satouchi K., Hanahan D. J., Pinckard R. N. Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues. Lab Invest. 1982 Apr;46(4):422–427. [PubMed] [Google Scholar]
  36. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  37. Lotner G. Z., Lynch J. M., Betz S. J., Henson P. M. Human neutrophil-derived platelet activating factor. J Immunol. 1980 Feb;124(2):676–684. [PubMed] [Google Scholar]
  38. Lynch J. M., Lotner G. Z., Betz S. J., Henson P. M. The release of a platelet-activating factor by stimulated rabbit neutrophils. J Immunol. 1979 Sep;123(3):1219–1226. [PubMed] [Google Scholar]
  39. Mencia-Huerta J. M., Benveniste J. Platelet-activating factor (PAF-acether) and macrophages. II. Phagocytosis-associated release of PAF-acether from rat peritoneal macrophages. Cell Immunol. 1981 Jan 15;57(2):281–292. doi: 10.1016/0008-8749(81)90087-3. [DOI] [PubMed] [Google Scholar]
  40. Mencia-Huerta J. M., Benveniste J. Platelet-activating factor and macrophages. I. Evidence for the release from rat and mouse peritoneal macrophages and not from mastocytes. Eur J Immunol. 1979 May;9(5):409–415. doi: 10.1002/eji.1830090512. [DOI] [PubMed] [Google Scholar]
  41. Mencia-Huerta J. M., Lewis R. A., Razin E., Austen K. F. Antigen-initiated release of platelet-activating factor (PAF-acether) from mouse bone marrow-derived mast cells sensitized with monoclonal IgE. J Immunol. 1983 Dec;131(6):2958–2964. [PubMed] [Google Scholar]
  42. Mencia-Huerta J. M., Ninio E., Roubin R., Benveniste J. Is platelet-activating factor (PAF-acether) synthesis by murine peritoneal cells (PC) a two-step process? Agents Actions. 1981 Dec;11(6-7):556–558. doi: 10.1007/BF01978738. [DOI] [PubMed] [Google Scholar]
  43. Mencia-Huerta J. M., Roubin R., Morgat J. L., Benveniste J. Biosynthesis of platelet-activating factor (PAF)acether). III. Formation of PAF-acether from synthetic substrates by stimulated murine macrophages. J Immunol. 1982 Aug;129(2):804–808. [PubMed] [Google Scholar]
  44. Ming W. J., Bersani L., Mantovani A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol. 1987 Mar 1;138(5):1469–1474. [PubMed] [Google Scholar]
  45. Ninio E., Mencia-Huerta J. M., Heymans F., Benveniste J. Biosynthesis of platelet-activating factor. I. Evidence for an acetyl-transferase activity in murine macrophages. Biochim Biophys Acta. 1982 Jan 15;710(1):23–31. doi: 10.1016/0005-2760(82)90185-0. [DOI] [PubMed] [Google Scholar]
  46. O'Flaherty J. T., Wykle R. L., Miller C. H., Lewis J. C., Waite M., Bass D. A., McCall C. E., DeChatelet L. R. 1-O-Alkyl-sn-glyceryl-3-phosphorylcholines: a novel class of neutrophil stimulants. Am J Pathol. 1981 Apr;103(1):70–78. [PMC free article] [PubMed] [Google Scholar]
  47. Pinckard R. N., Farr R. S., Hanahan D. J. Physicochemical and functional identity of rabbit platelet-activating factor (PAF) released in vivo during IgE anaphylaxis with PAF released in vitro from IgE sensitized basophils. J Immunol. 1979 Oct;123(4):1847–1857. [PubMed] [Google Scholar]
  48. Prescott S. M., Zimmerman G. A., McIntyre T. M. Human endothelial cells in culture produce platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when stimulated with thrombin. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3534–3538. doi: 10.1073/pnas.81.11.3534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Roubin R., Mencia-Huerta J. M., Landes A., Benveniste J. Biosynthesis of platelet-activating factor (PAF-acether). IV. Impairment of acetyl-transferase activity in thioglycollate-elicited mouse macrophages. J Immunol. 1982 Aug;129(2):809–813. [PubMed] [Google Scholar]
  50. Ruggiero V., Johnson S. E., Baglioni C. Protection from tumor necrosis factor cytotoxicity by protease inhibitors. Cell Immunol. 1987 Jul;107(2):317–325. doi: 10.1016/0008-8749(87)90240-1. [DOI] [PubMed] [Google Scholar]
  51. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  52. Shaw J. O., Pinckard R. N., Ferrigni K. S., McManus L. M., Hanahan D. J. Activation of human neutrophils with 1-O-hexadecyl/octadecyl-2-acetyl-sn-glycerol-3-phosphorylcholine (platelet activating factor). J Immunol. 1981 Sep;127(3):1250–1255. [PubMed] [Google Scholar]
  53. Smith R. A., Kirstein M., Fiers W., Baglioni C. Species specificity of human and murine tumor necrosis factor. A comparative study of tumor necrosis factor receptors. J Biol Chem. 1986 Nov 15;261(32):14871–14874. [PubMed] [Google Scholar]
  54. Sugarman B. J., Aggarwal B. B., Hass P. E., Figari I. S., Palladino M. A., Jr, Shepard H. M. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985 Nov 22;230(4728):943–945. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  55. Terashita Z., Imura Y., Nishikawa K., Sumida S. Is platelet activating factor (PAF) a mediator of endotoxin shock? Eur J Pharmacol. 1985 Feb 26;109(2):257–261. doi: 10.1016/0014-2999(85)90427-3. [DOI] [PubMed] [Google Scholar]
  56. Terashita Z., Tsushima S., Yoshioka Y., Nomura H., Inada Y., Nishikawa K. CV-3988 - a specific antagonist of platelet activating factor (PAF). Life Sci. 1983 Apr 25;32(17):1975–1982. doi: 10.1016/0024-3205(83)90049-8. [DOI] [PubMed] [Google Scholar]
  57. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  58. Tsujimoto M., Yokota S., Vilcek J., Weissmann G. Tumor necrosis factor provokes superoxide anion generation from neutrophils. Biochem Biophys Res Commun. 1986 Jun 30;137(3):1094–1100. doi: 10.1016/0006-291x(86)90337-2. [DOI] [PubMed] [Google Scholar]
  59. Vargaftig B. B., Chignard M., Benveniste J., Lefort J., Wal F. Background and present status of research on platelet-activating factor (PAF-acether). Ann N Y Acad Sci. 1981;370:119–137. doi: 10.1111/j.1749-6632.1981.tb29727.x. [DOI] [PubMed] [Google Scholar]
  60. Vilcek J., Palombella V. J., Henriksen-DeStefano D., Swenson C., Feinman R., Hirai M., Tsujimoto M. Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med. 1986 Mar 1;163(3):632–643. doi: 10.1084/jem.163.3.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  62. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Wykle R. L., Malone B., Snyder F. Enzymatic synthesis of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, a hypotensive and platelet-aggregating lipid. J Biol Chem. 1980 Nov 10;255(21):10256–10260. [PubMed] [Google Scholar]
  64. Yasaka T., Boxer L. A., Baehner R. L. Monocyte aggregation and superoxide anion release in response to formyl-methionyl-leucyl-phenylalanine (FMLP) and platelet-activating factor (PAF). J Immunol. 1982 May;128(5):1939–1944. [PubMed] [Google Scholar]

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