Skip to main content
Immunology logoLink to Immunology
. 1988 Jul;64(3):509–518.

Metabolism of leukotriene B4 by activated human polymorphonuclear granulocytes.

J Brom 1, W Schönfeld 1, W König 1
PMCID: PMC1385066  PMID: 2842254

Abstract

Human polymorphonuclear granulocytes (PMNs) synthesize leukotriene B4 (LTB4) as a response of cell activation. Inactivation of the potent inflammatory mediator proceeds via omega-oxidation, resulting in the formation of 20-hydroxy- and 20-carboxy-LTB4. The main metabolite after stimulation with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is 20-carboxy-LTB4, and after stimulation with the calcium ionophore A23187 is 20-hydroxy-LTB4. Differences in the LTB4 inactivation pathway were also observed when the catabolism of exogenously added LTB4 was analysed. In contrast to resting cells or cells preactivated with FMLP, prestimulation with the ionophore or with phorbol esters resulted in the inhibition of 20-carboxy-LTB4-generation. This decrease correlated with the reduction in specific [3H] LTB4-receptor expression. Studies with the non-penetrating diazonium salt of sulphanilic acid, which is known to interact with ectoenzymes, revealed that LTB4 is metabolized via receptor-mediated uptake. Our data suggest that the reduction in the amount of LTB4-receptor sites inhibits the conversion of 20-OH-LTB4 into 20-COOH-LTB4.

Full text

PDF
518

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson T., Dahlgren C., Lew P. D., Stendahl O. Cell surface expression of fMet-Leu-Phe receptors on human neutrophils. Correlation to changes in the cytosolic free Ca2+ level and action of phorbol myristate acetate. J Clin Invest. 1987 Apr;79(4):1226–1233. doi: 10.1172/JCI112941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrews P. C., Babior B. M. Endogenous protein phosphorylation by resting and activated human neutrophils. Blood. 1983 Feb;61(2):333–340. [PubMed] [Google Scholar]
  3. Berridge M. J. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J. 1984 Jun 1;220(2):345–360. doi: 10.1042/bj2200345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borgeat P., Samuelsson B. Metabolism of arachidonic acid in polymorphonuclear leukocytes. Structural analysis of novel hydroxylated compounds. J Biol Chem. 1979 Aug 25;254(16):7865–7869. [PubMed] [Google Scholar]
  5. Bray M. A. The pharmacology and pathophysiology of leukotriene B4. Br Med Bull. 1983 Jul;39(3):249–254. doi: 10.1093/oxfordjournals.bmb.a071828. [DOI] [PubMed] [Google Scholar]
  6. Bremm K. D., König W., Pfeiffer P., Rauschen I., Theobald K., Thelestam M., Alouf J. E. Effect of thiol-activated toxins (streptolysin O, alveolysin, and theta toxin) on the generation of leukotrienes and leukotriene-inducing and -metabolizing enzymes from human polymorphonuclear granulocytes. Infect Immun. 1985 Dec;50(3):844–851. doi: 10.1128/iai.50.3.844-851.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Breuer O., Hammarström S. Enzymatic conversion of leukotriene B4 to 6-trans-leukotriene B4 by rat kidney homogenates. Biochem Biophys Res Commun. 1987 Feb 13;142(3):667–673. doi: 10.1016/0006-291x(87)91466-5. [DOI] [PubMed] [Google Scholar]
  8. Brom J., König W., Stüning M., Raulf M., Köller M. Characterization of leukotriene B4-omega-hydroxylase activity within human polymorphonuclear granulocytes. Scand J Immunol. 1987 Mar;25(3):283–294. doi: 10.1111/j.1365-3083.1987.tb01074.x. [DOI] [PubMed] [Google Scholar]
  9. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  10. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847–7851. [PubMed] [Google Scholar]
  11. Clancy R. M., Dahinden C. A., Hugli T. E. Oxidation of leukotrienes at the omega end: demonstration of a receptor for the 20-hydroxy derivative of leukotriene B4 on human neutrophils and implications for the analysis of leukotriene receptors. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5729–5733. doi: 10.1073/pnas.81.18.5729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cockcroft S., Gomperts B. D. Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase. Nature. 1985 Apr 11;314(6011):534–536. doi: 10.1038/314534a0. [DOI] [PubMed] [Google Scholar]
  13. DePierre J. W., Karnovsky M. L. Ecto-enzymes of the guinea pig polymorphonuclear leukocyte. I. Evidence for an ecto-adenosine monophosphatase, adenosine triphosphatase, and -p-nitrophenyl phosphates. J Biol Chem. 1974 Nov 25;249(22):7111–7120. [PubMed] [Google Scholar]
  14. Della Bianca V., De Togni P., Grzeskowiak M., Vicentini L. M., Di Virgilio F. Cyclic AMP inhibition of phosphoinositide turnover in human neutrophils. Biochim Biophys Acta. 1986 May 29;886(3):441–447. doi: 10.1016/0167-4889(86)90180-1. [DOI] [PubMed] [Google Scholar]
  15. Goldman D. W., Goetzl E. J. Specific binding of leukotriene B4 to receptors on human polymorphonuclear leukocytes. J Immunol. 1982 Oct;129(4):1600–1604. [PubMed] [Google Scholar]
  16. Hansson G., Lindgren J. A., Dahlén S. E., Hedqvist P., Samuelsson B. Identification and biological activity of novel omega-oxidized metabolites of leukotriene B4 from human leukocytes. FEBS Lett. 1981 Jul 20;130(1):107–112. doi: 10.1016/0014-5793(81)80676-x. [DOI] [PubMed] [Google Scholar]
  17. Harper T. W., Garrity M. J., Murphy R. C. Metabolism of leukotriene B4 in isolated rat hepatocytes. Identification of a novel 18-carboxy-19,20-dinor leukotriene B4 metabolite. J Biol Chem. 1986 Apr 25;261(12):5414–5418. [PubMed] [Google Scholar]
  18. Horn W., Karnovsky M. L. Features of the translocation of protein kinase C in neutrophils stimulated with the chemotactic peptide f-Met-Leu-Phe. Biochem Biophys Res Commun. 1986 Sep 30;139(3):1169–1175. doi: 10.1016/s0006-291x(86)80300-x. [DOI] [PubMed] [Google Scholar]
  19. Kaever V., Martin M., Fauler J., Marx K. H., Resch K. A novel metabolic pathway for leukotriene B4 in different cell types: primary reduction of a double bond. Biochim Biophys Acta. 1987 Dec 14;922(3):337–344. doi: 10.1016/0005-2760(87)90056-7. [DOI] [PubMed] [Google Scholar]
  20. Lefer A. M. Leukotrienes as mediators of ischemia and shock. Biochem Pharmacol. 1986 Jan 15;35(2):123–127. doi: 10.1016/0006-2952(86)90502-2. [DOI] [PubMed] [Google Scholar]
  21. Lin A. H., Ruppel P. L., Gorman R. R. Leukotriene B4 binding to human neutrophils. Prostaglandins. 1984 Dec;28(6):837–849. doi: 10.1016/0090-6980(84)90038-8. [DOI] [PubMed] [Google Scholar]
  22. Lindgren J. A., Hansson G., Samuelsson B. Formation of novel hydroxylated eicosatetraenoic acids in preparations of human polymorphonuclear leukocytes. FEBS Lett. 1981 Jun 15;128(2):329–335. doi: 10.1016/0014-5793(81)80110-x. [DOI] [PubMed] [Google Scholar]
  23. Marcus A. J., Safier L. B., Ullman H. L., Islam N., Broekman M. J., von Schacky C. Studies on the mechanism of omega-hydroxylation of platelet 12-hydroxyeicosatetraenoic acid (12-HETE) by unstimulated neutrophils. J Clin Invest. 1987 Jan;79(1):179–187. doi: 10.1172/JCI112781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. May W. S., Sahyoun N., Jacobs S., Wolf M., Cuatrecasas P. Mechanism of phorbol diester-induced regulation of surface transferrin receptor involves the action of activated protein kinase C and an intact cytoskeleton. J Biol Chem. 1985 Aug 5;260(16):9419–9426. [PubMed] [Google Scholar]
  25. McPhail L. C., Snyderman R. Activation of the respiratory burst enzyme in human polymorphonuclear leukocytes by chemoattractants and other soluble stimuli. Evidence that the same oxidase is activated by different transductional mechanisms. J Clin Invest. 1983 Jul;72(1):192–200. doi: 10.1172/JCI110957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Naccache P. H., Molski T. F., Borgeat P., Sha'afi R. I. Association of leukotriene B4 with the cytoskeleton of rabbit neutrophils. Effect of chemotactic factor and phorbol esters. Biochem Biophys Res Commun. 1984 Nov 14;124(3):963–969. doi: 10.1016/0006-291x(84)91052-0. [DOI] [PubMed] [Google Scholar]
  27. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  28. O'Flaherty J. T., Nishihira J. Arachidonate metabolites, platelet-activating factor, and the mobilization of protein kinase C in human polymorphonuclear neutrophils. J Immunol. 1987 Mar 15;138(6):1889–1895. [PubMed] [Google Scholar]
  29. O'Flaherty J. T., Redman J. F., Jacobson D. P. Protein kinase C regulates leukotriene B4 receptors in human neutrophils. FEBS Lett. 1986 Oct 6;206(2):279–282. doi: 10.1016/0014-5793(86)80996-6. [DOI] [PubMed] [Google Scholar]
  30. O'Flaherty J., Kosfeld S., Nishihira J. Binding and metabolism of leukotriene B4 by neutrophils and their subcellular organelles. J Cell Physiol. 1986 Mar;126(3):359–370. doi: 10.1002/jcp.1041260306. [DOI] [PubMed] [Google Scholar]
  31. Orning L. Omega-hydroxylation of N-acetylleukotriene E4 by rat liver microsomes. Biochem Biophys Res Commun. 1987 Feb 27;143(1):337–344. doi: 10.1016/0006-291x(87)90670-x. [DOI] [PubMed] [Google Scholar]
  32. Paterson N. A. Metabolism of leukotriene D4 by porcine alveolar macrophages. Am Rev Respir Dis. 1984 Feb;129(2):274–278. [PubMed] [Google Scholar]
  33. Powell W. S. Novel pathway for the metabolism of 6-trans-leukotriene B4 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun. 1986 Apr 29;136(2):707–712. doi: 10.1016/0006-291x(86)90497-3. [DOI] [PubMed] [Google Scholar]
  34. Preiss J. E., Bell R. M., Niedel J. E. Diacylglycerol mass measurements in stimulated HL-60 phagocytes. J Immunol. 1987 Mar 1;138(5):1542–1545. [PubMed] [Google Scholar]
  35. Prentki M., Wollheim C. B., Lew P. D. Ca2+ homeostasis in permeabilized human neutrophils. Characterization of Ca2+-sequestering pools and the action of inositol 1,4,5-triphosphate. J Biol Chem. 1984 Nov 25;259(22):13777–13782. [PubMed] [Google Scholar]
  36. Raulf M., Stüning M., König W. Metabolism of leukotrienes by L-gamma-glutamyl-transpeptidase and dipeptidase from human polymorphonuclear granulocytes. Immunology. 1985 May;55(1):135–147. [PMC free article] [PubMed] [Google Scholar]
  37. Schell-Frederick E. A comparison of the effects of soluble stimuli on free cytoplasmic and membrane bound calcium in human neutrophils. Cell Calcium. 1984 Jun;5(3):237–251. doi: 10.1016/0143-4160(84)90039-3. [DOI] [PubMed] [Google Scholar]
  38. Sekar M. C., Hokin L. E. The role of phosphoinositides in signal transduction. J Membr Biol. 1986;89(3):193–210. doi: 10.1007/BF01870664. [DOI] [PubMed] [Google Scholar]
  39. Serafin W. E., Oates J. A., Hubbard W. C. Metabolism of leukotriene B4 in the monkey. Identification of the principal nonvolatile metabolite in the urine. Prostaglandins. 1984 Jun;27(6):899–911. doi: 10.1016/s0090-6980(84)80009-x. [DOI] [PubMed] [Google Scholar]
  40. Shak S., Goldstein I. M. Leukotriene B4 omega-hydroxylase in human polymorphonuclear leukocytes. Partial purification and identification as a cytochrome P-450. J Clin Invest. 1985 Sep;76(3):1218–1228. doi: 10.1172/JCI112077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sumimoto H., Takeshige K., Minakami S. NAD+-dependent conversion of 20-OH-LTB4 to 20-COOH-LTB4 by a cell-free system of human polymorphonuclear leukocytes. Biochem Biophys Res Commun. 1985 Nov 15;132(3):864–870. doi: 10.1016/0006-291x(85)91887-x. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES