Skip to main content
Log in

The arachidonate 12/15 lipoxygenases

A review of tissue expression and biologic function

  • Basic Sciences
  • The Immunobiology of Leukotriene Inhibitors
  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Summary

12/15-Lipoxygenase is a highly regulated lipid-peroxidating enzyme whose expression and arachidonic acid metabolites are implicated in several important inflammatory conditions including airway and glomerular inflammation as well as atherosclerosis. Tissue expression of the original 12/15-lipoxygenase is well characterized in reticulocytes, eosinophils, airway epithelial cells, and monocytes/macrophages and is likely in other cell systems and tissues under specific conditions. The physiologic role of this family of enzymes is dependent on the context in which it is expressed. In general, the arachidonic acid metabolites antagonize inflammatory responses and counteract the proinflammatory effects of the 5-lipoxygenase pathway. However, certain diHETEs are associaled with pro-inflammatory effects, specifically neutrophilic and eosiniphilic chemotaxis. The direct action of these enzymes on complex lipids and cellular membranes also links them to such significant process as reticulocyte maturation, LDL oxidation in atherosclerosis and pulmonary host defenses. The availability of new specific inhibitors and murine lines that lack expression of the homologous 12-lipoxygenase will allow confirmation of many of these effects with in vivo models of inflammation.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 1987; 237(4819):1171–1176.

    PubMed  CAS  Google Scholar 

  2. Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Glass CK, Sigal E, Witztum JL, Steinberg D. Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions. Proc Natl Acad Sci USA 1990;87(18):6959–6963.

    PubMed  CAS  Google Scholar 

  3. Badr KF, Lakkis FG. Lipoxygenase products in normal and diseased glomeruli. Ann NY Acad Sci 1994;744:216–228.

    PubMed  CAS  Google Scholar 

  4. Sigal E, Nadel JA. Arachidonic acid 15-lipoxygenase and airway epithelium. Biologic effects and enzyme purification. Am Rev Respir Dis 1988;138(6 Pt 2):S35–40.

    Google Scholar 

  5. Brash AR, Boeglin WE, Chang MS. Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci USA 1997;94(12):6148–6152.

    PubMed  CAS  Google Scholar 

  6. Sloane D. Exploring the structure and function of mammalian lipoxygenases by site directed mutagenesis. In: Piazza G ed. Lipoxygenase and Lipoxygenase Pathway Enzymes. Champaign, Illinois: AOCS Press 1996; pp. 57–79.

    Google Scholar 

  7. Prigge ST, Boyington JC, Gaffney BJ, Amzel LM. Structure conservation in lipoxygenases: structural analysis of soybean lipoxygenase-1 and modeling of human lipoxygenases. Proteins 1996;24(3):275–291.

    PubMed  CAS  Google Scholar 

  8. Nadel JA, Conrad DJ, Ueki IF, Schuster A, Sigal E. Immunocytochemical localization of arachidonate 15-lipoxygenase in erythrocytes, leukocytes, and airway cells. J Clin Invest 1991;87(4):1139–1145.

    PubMed  CAS  Google Scholar 

  9. Brinckmann R, Topp MS, Zalan I, Heydeck D, Ludwig P, Kuhn H, Berdel WE. Regulation of 15-lipoxygenase expression in lung epithelial cells by interleukin-4. Biochem J 1996;318(Pt 1):305–312.

    PubMed  CAS  Google Scholar 

  10. Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci USA 1992;89(1):217–221.

    PubMed  CAS  Google Scholar 

  11. Rapoport SM, Schewe T, Wiesner R, Halangk W, Ludwig P, Janicke-Hohne M, Tannert C. the lipoxygenase of reticulocytes. Purification, characterization and biological dynamics of the lipoxygenase; its identity with the respiratory inhibitors of the reticulocyte. Eur J Biochem 1979;96(3):545–561.

    PubMed  CAS  Google Scholar 

  12. Sigal E, Dicharry S, Highland E, Finkbeiner WE. Cloning of human airway 15 lipoxygenase: identity to the reticulocyte enzyme and expression in epithelium. Am J Physiol 1992;262(4 Pt 1):L392–398.

    PubMed  CAS  Google Scholar 

  13. Sigal E, Grunberger D, Highland E, Gross C, Dixon RA, Craik CS. Expression of cloned human reticulocyte 15-lipoxygenase and immunological evidence that 15-lipoxygenases of different cell types are related. J Biol Chem 1990;265(9):5113–5120.

    PubMed  CAS  Google Scholar 

  14. Sigal E, Grunberger D, Craik CS, Caughey GH, Nadel JA. Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases. J Biol Chem 1988;263(11):5328–5332.

    PubMed  CAS  Google Scholar 

  15. Larrue J, Rigaud M, Razaka G, Daret D, Demond-Henri J, Bricaud H. Formation of monohydroxyeicosatetraenoic acids from arachidonic acid by cultured rabbit aortic smooth muscle cells. Biochem Biophys Res Commun 1983;112(1):242–249.

    PubMed  CAS  Google Scholar 

  16. Hugou I, Thin P, Henri J, Daret D, Larrue J. 15-Lipoxygenase expression in smooth muscle cells from atherosclerotic rabbit aortas. Atherosclerosis 1995; 113(2):189–195.

    PubMed  CAS  Google Scholar 

  17. Hopkins NK, Oglesby TD, Bundy GL, Gorman RR. Biosynthesis and metabolism of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid by human umbilical vein endothelial cells. J Biol Chem 1984;259(22):14,048–14,053.

    CAS  Google Scholar 

  18. Lopez S, Vila L, Breviario F, de Castellarnau C. Interleukin-1 increases 15-hydroxyeicosatetraenoic acid formation in cultured human endothelial cells. Biochim Biophys Acta 1993;1170(1):17–24.

    PubMed  CAS  Google Scholar 

  19. Omura M, Hirai A, Tamura Y, Yoshida S. Transformation of arachidonic acid by 5- and 15-lipoxygenase pathways in bovine adrenal fasciculata cells. Prostaglandins Leukot Essent Fatty Acids 1990;40(2):93–102.

    PubMed  CAS  Google Scholar 

  20. Lei ZM, Rao CV. The expression of 15-lipoxygenase gene and the presence of functional enzyme in cytoplasm and nuclei of pregnancy human myometria. Endocrinology 1992;130(2):861–870.

    PubMed  CAS  Google Scholar 

  21. Burrall BA, Cheung M, Chiu A, Goeltzl EJ. Enzymatic properties of the 15-lipoxygenase of human cultured keratinocytes. J Invest Dermatol 1988; 91(4):294–297.

    PubMed  CAS  Google Scholar 

  22. Zhao H, Richards-Smith B, Baer AN, Green FA. Lipoxygenase mRNA in cultured human epidermal and oral keratinocytes. J Lipid Res 1995;36(11):2444–2449.

    PubMed  CAS  Google Scholar 

  23. Kuhn H, Brash AR. Occurrence of lipoxygenase products in membranes of rabbit reticulocytes. Evidence for a role of the reticulocyte lipoxygenase in the maturation of red cells. J Biol Chem 1990;265(3):1454–1458.

    PubMed  CAS  Google Scholar 

  24. Kroschwald P, Kroschwald A, Kuhn H, Ludwig P, Thiele BJ, Hohne M, Schewe T. Occurrence of the erythroid cell specific arachidonate 15-lipoxygenase in human reticulocytes. Biochem Biophys Res Commun 1989;160(2):954–960.

    PubMed  CAS  Google Scholar 

  25. Turk J, Maas RL, Brash AR, Roberts LJD, Oates JA. Arachidonic acid 15-lipoxygenase products from human eosinophils. J Biol Chem 1982;257(12):7068–7076.

    PubMed  CAS  Google Scholar 

  26. Henderson WR, Harley JB, Fauci A. Arachidonic acid metabolism in normal and hypereosinophilic syndrome human eosinophils: generation of leukotrienes B4, C4, D4 and 15-lipoxygenase products. Immunology 1984;51(4):679–686.

    PubMed  CAS  Google Scholar 

  27. Bradding P, Redington AK, Djukanovic R, Conrad DJ, Holgate ST. 15-lipoxygenase immunoreactivity in normal and in asthmatic airways. Am J Respir Crit Care Med 1995;151(4):1201–1204.

    PubMed  CAS  Google Scholar 

  28. Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Sigal E, Sarkioja T, Witztum JL, Steinberg D. Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts. J Clin Invest 1991;87(4):1146–1152.

    PubMed  CAS  Google Scholar 

  29. Ravalli S, Marboe CC, D’Agati VD, Michler RE, Sigal E, Cannon PJ. Immunohistochemical demonstration of 15-lipoxygenase in transplant coronary artery disease. Arterioscler Thromb Vasc Biol 1995;15(3):340–348.

    PubMed  CAS  Google Scholar 

  30. Nassar GM, Morrow JD, Roberts LJD, Lakkis FG, Badr KF. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. J Biol Chem 1994;269(44):27,631–27,634.

    CAS  Google Scholar 

  31. Natarajan R, Gonzales N, Lanting L, Nadler J. Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy. Hypertension 1994;23(1 Suppl):1142–1147.

    Google Scholar 

  32. Scheidegger KJ, Butler S, Witztum JL. Angiotensin II increases macrophage-mediated modification of low density lipoprotein via a lipoxygenase-dependent pathway. J Biol Chem 1997;272(34):21,609–21,615.

    CAS  Google Scholar 

  33. Reddy N, Everhart A, Eling T, Glasgow W. Characterization of a 15-lipoxygenase in human breast carcinoma BT-20 cells: stimulation of 13-HODE formation by TGF alpha/EGF. Biochem Biophys Res Commun 1997;231(1):111–116.

    PubMed  CAS  Google Scholar 

  34. O’Prey J, Chester J, Thiele BJ, Janetzki S, Prehn S, Fleming J, Harrison PR. The promoter structure and complete sequence of the gene encoding the rabbit erythroid cellspecific 15-lipoxygenase. Gene 1989;84(2):493–499.

    PubMed  CAS  Google Scholar 

  35. O’Prey J, Harrison PR. Tissue-specific regulation of the rabbit 15-lipoxygenase gene in erythroid cells by a transcriptional silencer. Nucleic Acids Res 1995; 23(18):3664–3672.

    PubMed  CAS  Google Scholar 

  36. Kritzik MR, Ziober AF, Dicharry S, Conrad DJ, Sigal E. Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene. Biochim Biophys Acta 1997;1352(3):267–281.

    PubMed  CAS  Google Scholar 

  37. Fleming J, Thiele BJ, Chester J, O’Prey J, Janetzki S, Aitken A, Anton IA. The complete sequence of the rabbit erythroid cell-specific 15-lipoxygenase mRNA: comparison of the predicted amino acid sequence of the erythrocyte lipoxygenase with other lipoxygenases. Gene 1989;79(1):181–188.

    PubMed  CAS  Google Scholar 

  38. Thiele BJ, Fleming J, Chester J, O’Frey J, Prehn S, Janetzki S, Rapoport SM. Structure of the mRNA and of the gene coding for the rabbit erythroid 15-lipoxygenase. Biomed Biochim. Acta 1990;49(2–3):S17–24.

    Google Scholar 

  39. Ostareck-Lederer A, Ostareck DH, Standart N, Thiele BJ. Translation of 15-lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3′-untranslated region. EMBO J 1994;13(6):1476–1481.

    PubMed  CAS  Google Scholar 

  40. Ostareck DH, Ostareck-Lederer A, Wilm M, Thiele BJ, Mann M, Hentze MW. mRNA silencing in erythroid differentiation: hnRNPK and hnRNP E1regulate 15-lipoxygenase translation from the 3′ end. Cell 1997;89(4):597–606.

    PubMed  CAS  Google Scholar 

  41. Hartel B, Ludwig P, Schewe T, Rapoport SM. Self-inactivation by 13-hydroperoxylinoleic acid and lipohydroperoxidase activity of the reticulocyte lipoxygenase. Eur J Biochem 1982;126(2):353–357.

    PubMed  CAS  Google Scholar 

  42. Schewe T, Rapoport SM, Kuhn H. Enzymology and physiology of reticulocyte lipoxygenase: comparison with other lipoxygenases. Adv Enzymol Relat Areas Mol Biol 1986;58:191–272.

    PubMed  CAS  Google Scholar 

  43. Rapoport S, Hartel B, Hausdorf G. Methionine sulfoxide formation: the cause of self inactivation of reticulocyte lipoxygenase. Eur J Biochem 1984;139(3):573–576.

    PubMed  CAS  Google Scholar 

  44. Gan QF, Witkop GL, Sloane DL, Straub KM, Sigal E. Identification of a specific methionine in mammalian 15-lipoxygenase which is oxygenated by the enzyme product 13-HPODE: dissociation of sulfoxide formation from self-inactivation. Biochemistry 1995;34(21):7069–7079.

    PubMed  CAS  Google Scholar 

  45. Bongrazio M, Roscher A, Ludwig P, Nigam S. Loss of cytosolic 15-lipoxygenase activity in A23187-stimulated human leukocytes: involvement of a translocation process. Eicosanoids 1992;5(3–4):191–195.

    PubMed  CAS  Google Scholar 

  46. Watson A, Doherty FJ. Calcium promotes membrane association of reticulocyte 15-lipoxygenase. Biochem J 1994;298(Pt 2):377–383.

    PubMed  CAS  Google Scholar 

  47. Kuhn H, Belkner J, Wiesner R, Brash AR. Oxygenation of biological membranes by the pure reticulocyte lipoxygenase. J Biol Chem 1990;265(30):18,351–18,361.

    CAS  Google Scholar 

  48. Kuhn H, Sprecher H, Brash AR. On singular or dual positional specificity of lipoxygenases. The number of chiral products varies with alignment of methylene groups at the activesite of the enzyme. J Biol Chem 1990;265(27):16,300–16,305.

    CAS  Google Scholar 

  49. Vanderhoek JY, Bryant RW, Bailey JIM. Inhibition of leukotriene biosynthesis by the leukocyte product 15-hydroxy-5,8,11,13-eicosatetraenoic acid. J Biol Chem 1980;255(21):10,064–10,066.

    CAS  Google Scholar 

  50. Vanderhoek JY, Bryant RW, Bailey JRJI. Regulation of leukocyte and platelet lipoxygenases by hydroxyeicosanoids. Biochem Pharmacol 1982; 31(21):3463–3467.

    PubMed  CAS  Google Scholar 

  51. Low CE, Pupillo MB, Bryant RW, Bailey JM. Inhibition of phytohemaglutinin-induced Iymphocyte mitogenesis by lipoxygenase metabolites of arachidonic acid: structure-activity relationships. J Lipid Res 1984;25(10):1090–1095.

    PubMed  CAS  Google Scholar 

  52. Bruynzeel PL., Kok PT, Vietor RJ, Verhagen J. On the optimal conditions of LTC4 formation by human eosinophils in vitro. F’rostaglandins Leukot Med 1985;20(1):11–22.

    CAS  Google Scholar 

  53. Takata S, Papayianni A, Matsubara M, Jimenez W, Pronovost PH, Brady HR. 15-Hydroxyeicosatetraenoic acid inhibits neutrophil migration across cytokine-activated endothelium. Am J Pathol 1994;145(3):541–549.

    PubMed  CAS  Google Scholar 

  54. Smith RJ, Justen JM, Nidy KG, Saml M, Bleasdale JE. Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation. Proc Natl Acad Sci USA 1993;90(15):7270–7274.

    PubMed  CAS  Google Scholar 

  55. Goodwin JS, Gualde N, Aldigier J, Rigaud M, Vanderhoek JY. Modulation of Fc gamma receptors on I cells and monocytes by 15-hydroperoxyeicosatetranoic acid. Prostaglandins Leukot Med 1984;13(1):109–112.

    PubMed  CAS  Google Scholar 

  56. Ramstedt U, Serhan CN, Lundberg U, Wigzell H, Samuelsson B. Inhibition of human natural killer cell activity by (14R, 15S)-14,15-dihydroxy-5Z,8Z,10E,12E-icosatetraenoic acid. Proc Natl Acad Sci USA 1984;81(22):6914–6918.

    PubMed  CAS  Google Scholar 

  57. Ramstedt U, Ng J, Wigzell H, Serhan CN, Samuelsson B. Action of novel eicosanoids lipoxin A and B on human natural killer cell cytotoxicity: effects on intracellular cAMP and target cell binding. J Immunol 1985;135(5):3434–3438.

    PubMed  CAS  Google Scholar 

  58. Ferrante JV, Huang ZH, Nandoskar M, Hii CS, Robinson BS, Rathjen Dajpoulos A. Altered responses of human macrophages to lipopolysaccharide by hydroperoxy eicosatetraenoic acid, hydroxy eicosatetraenoic acid, and arachidonic acid. Inhibition of tumor necrosis factor production. J Clin Invest 1997;99(6): 1445–1452.

    PubMed  CAS  Google Scholar 

  59. Huang ZH, Bates EJ, Ferrante JV, Hii CS, Poulos A, Robinson BS, Ferrante A. Inhibition of stimulus-induced endothelial cell intercellular adhesion molecule-1, E-selectin, and vascular cellular adhesion molecule-1 expression by arachidonic acid and its hydroxy and hydroperoxy derivatives. Circ Res 1997;80(2):149–158.

    PubMed  CAS  Google Scholar 

  60. Shak S, Perez HD, Goldstein IM. A novel dioxygenation product of arachidonic acid possesses potent chemotactic activity for human polymorphonuclear leukocytes. J Biol Chem 1983;258(24):14,948–14,953.

    CAS  Google Scholar 

  61. Kirsch CM, Sigal E, Djokic TD, Graf PD, Nadel JA. An in vivo chemotaxis assay in the dog trachea: evidence for chemotactic activity of 8,15-diHETE. J Appl Physiol 1988;64(5):17,925.

    Google Scholar 

  62. Morita E, Schroder JM, Christophers E. Identification of a novel and highly potent eosinophil chemotactic lipid in human eosinophils treated with arachidonic acid. J Immunol 1990;144(5):1893–1900.

    PubMed  CAS  Google Scholar 

  63. Schwenk U, Morita E, Engel R, Schroder JM. Identification of 5-oxo-15-hydroxy 6,8,11,13-eicosatetraenoic acid as a novel and potent human eosinophil chemotactic eicosanoid. J Biol Chem 1992;267(18):12,482–12,488.

    CAS  Google Scholar 

  64. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirintriggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med 1997;185(9):1693–1704.

    PubMed  CAS  Google Scholar 

  65. Fiore S, Maddox JF, Perez HD, Serhan CN. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J Exp Med 1994;180(1):253–260.

    PubMed  CAS  Google Scholar 

  66. Edenius C, Kumlin M, Bjork T, Anggard A, Lindgren JA. Lipoxin formation in human nasal polyps and bronchial tissue. FEBS Lett 1990;272(1–2):25–28.

    PubMed  CAS  Google Scholar 

  67. Papayianni A, Serhan CN, Phillips ML, Rennke HG, Brady HR. Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis. Kidney Int 1995;47(5):1295–1302.

    PubMed  CAS  Google Scholar 

  68. Serhan CN. Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim Biophys Acta 1994;1212(1):1–25.

    PubMed  CAS  Google Scholar 

  69. Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci USA 1984;81(17):5335–5339.

    PubMed  CAS  Google Scholar 

  70. Hansson A, Serhan CN, Haeggstrom J, Ingelman-Sundberg M, Samuelsson B. Activation of protein kinase C by lipoxin A and other eicosanoids. Intracellular action of oxygenation products of arachidonic acid. Biochem Biophys Res Commun 1986;134(3):1215–1222.

    PubMed  CAS  Google Scholar 

  71. Dahlen S, Serhan C. In: Wang A, Crooke S, eds. Lipoxygenases and Their Products. Academic, CA, 1991:235–276.

    Google Scholar 

  72. Christie PE, Spur BW, Lee TH. The effects of lipoxin A4 on airway responses in asthmatic subjects. Am Rev Respir Dis 1992;145(6):1281–1284.

    PubMed  CAS  Google Scholar 

  73. Lee TH, Lympany P, Crea AK, Spur BW. Inhibition of leukotriene B4-induced neutrophil migration by lipoxin A4: structure-function relationships. Biochem Biophys Res Commun 1991;180(3):1416–1421.

    PubMed  CAS  Google Scholar 

  74. Papayianni A, Serhan CN, Brady HR. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J Immunol 1996;156(6):2264–2272.

    PubMed  CAS  Google Scholar 

  75. Colgan SP, Serhan CN, Parkos CA, Delp-Archer C, Madara JL. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J Clin Invest 1993;92(1):75–82.

    PubMed  CAS  Google Scholar 

  76. Legrand AB, Lawson JA, Meyrick BC, Blair IA, Oates JA. Substitution of 15-hydroxyeicosatetraenoic acid in the phosphoinositide signaling pathway. J Biol Chem 1991;266(12):7570–7577.

    PubMed  CAS  Google Scholar 

  77. Bates EJ, Ferrante A, Poulos A, Smithers L, Rathjen DA, Robinson BS. Inhibitory effects of arachidonic acid (20:4, n−6) and its monohydroperoxy- and hydroxy-metabolites on procoagulant activity in endothelial cells. Atherosclerosis 1995;116(1):125–133.

    PubMed  CAS  Google Scholar 

  78. Wallukat G, Morwinski R, Kuhn H. Modulation of the beta-adrenergic response of cardiomyocytes by specific lipoxygenase products involves their incorporation into phosphatidylinositol and activation of protein kinase C. J Biol Chem 1994;269(46):29,055–29,060.

    CAS  Google Scholar 

  79. Timar J, Raso E, Fazakas ZS, Silletti S, Raz A, Honn KV. Multiple use of a signal transduction pathway in tumor cell invasion. Anticancer Res 1996;16(6A):3299–3306.

    PubMed  CAS  Google Scholar 

  80. Timar J, Trikha M, Szekeres K, Bazaz R, Tovari J, Silletti S, Raz A. Autocrine motility factor signals integrin-mediated metastatic melanoma cell adhesion and invasion. Cancer Res 1996;56(8):1902–1908.

    PubMed  CAS  Google Scholar 

  81. Tang DG, Tarrien M, Dobrzynski P, Honn KV. Melanoma cell spreading on fibronectin induced by 12(S)-HETE involves both protein kinase C-and protein tyrosine kinase-dependent focal adhesion formation and tyrosine phosphorylation of focal adhesion kinase (pp125FAK). J Cell Physiol 1995;165(2):291–306.

    PubMed  CAS  Google Scholar 

  82. Tang DG, Diglio CA, Honn KV. Activation of microvascular endothelium by eicosanoid 12(S)-hydroxyeicosatetraenoic acid leads to enhanced tumor cell adhesion via up-regulation of surface expression of alpha v beta 3 integrin: a posttranscriptional, protein kinase C- and cytoskeleton-dependent process. Cancer Res 1994;54(4):1119–1129.

    PubMed  CAS  Google Scholar 

  83. Rao GN, Baas AS, Glasgow WC, Elingl TE, Runge MS, Alexander RW. Activation of mitogen activated protein kineses by arachidonic acid and its metabolites in vascular smooth muscle cells. J Biol Chem 1994;269(51):32,586–32,591.

    CAS  Google Scholar 

  84. Glasgow WC, Hui R, Everhart AL, Jayawickreme SP, Angerman-Stewart J, Han BB, Eling TE. The linoleic acid metabolite, (13S)-hydroperoxyoctadecadienoic acid, augments the epidermal growth factor receptor signaling pathway by attenuation of receptor dephosphorylation. Differential response in Syrian hamster embryo tumor suppressor phenotypes. J Biol Chem 1997;272(31):119,269–119,276.

    Google Scholar 

  85. Eager NS, Brickell PM, Snell C, Wood JN. Structural and functional evidence for activation of a chick retinoid X receptor by eicosanoids. Proc R Soc Lond B Biol Sci 1992;250(1327):63–69.

    CAS  Google Scholar 

  86. Tontonez P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, Brun RP, Mueller E, Altiok S, Oppenheim H, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferation-activated receptor gamma and the reinoid X receptor. Proc Natl Acad Sci USA 1997; 94(1):237–241.

    Google Scholar 

  87. Yamamoto S, Ishii M, Nakadate T, Nakaki T, Kato R. Modulation of insulin secretion by lipoxygenase products of arachidonic acid. Relation to lipoxygenase activity of pancreatic islets. J Biol Chem 1983;258(20):12,149–12,152.

    CAS  Google Scholar 

  88. Metz SA, Murphy RC, Fujimoto W. Effects on glucose-induced insulin secretion of lipoxygenase-derived metabolites of arachidonic acid. Diabetes 1984; 33(2):119–124.

    PubMed  CAS  Google Scholar 

  89. Rabier M, Chavis C, Crastes de Paulet A, Damon M. 15-Lipoxygenase products stimulate prolactin secretion from a cloned strain of rat pituitary cells. Neuroendocrinology 1988;47(4):323–328.

    PubMed  CAS  Google Scholar 

  90. Lax Y, Grossman S, Rubinstein S, Magid N, Breitbart H. Role of lipoxygenase in the mechanism of acrosome reaction in mammalian spermatozoa. Biochim Biophys Acta 1990;1043(1):12–18.

    PubMed  CAS  Google Scholar 

  91. Edwin SS, Mitchell MD. Arachidonate lipoxygenase metabolite formation in gestational tissues. J Lipid Mediat Cell Signal 1994;13(3):291–300.

    Google Scholar 

  92. Kuhn H, Belkner J, Zaiss S, Fahrenklemper T, Wohifeil S. Involvement of 15-lipoxygenase in early stages of atherogenesis. J Exp Med 1994;179(6):1903–1911.

    PubMed  CAS  Google Scholar 

  93. Sigal E, Sloane DL, Conrad DJ. Human 15-lipoxygenase: induction by interleukin-4 and insights into positional specificity. J Lipid Mediat 1993;6(1–3):75–88.

    PubMed  CAS  Google Scholar 

  94. Schnurr K, Hellwing M, Seidemann B, Jungblut P, Kuhn H, Rapoport SM, Schewe T. Oxygenation of biomembranes by mammalian lipoxygenases: the role of ubiquinone. Free Radic Biol Med 1996;20(1):11–21.

    PubMed  CAS  Google Scholar 

  95. Postoak D, Nystuen L, King L, Ueno HA, Beckman BS. 15-Lipoxygenase products of arachidonate play a role in proliferation of transformed erythroid cells. Am J Physiol 1990;259(6 Pt 1):C849–853.

    PubMed  CAS  Google Scholar 

  96. van Leyen K, Duvoisin RM, Engelhardt H, Wiedmann M. A function for lipoxygenase in programmed organelle degradation. Nature 1998;395(6700):392–395.

    PubMed  Google Scholar 

  97. Sendobry SM, Cornicelli JA, Welch K, Bocan T, Tait B, Trivedi BK, Colbry N. Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties. Br J Pharmacol 1997;120(7):1199–1206.

    PubMed  CAS  Google Scholar 

  98. Sun D, Funk CD. Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein. J Biol Chem 1936;271(39):24,055–24,062.

    Google Scholar 

  99. O’Bryrne PM, Leikauf GD, Aizawa H, Bethel RA, Ueki IF, Holtzman MJ, Nadel JA. Leukotriene B4 induces airway hyperresponsiveness in dogs. J Appl Physiol 1985;59(6):1941–1946.

    Google Scholar 

  100. Holtzman MJ, Aizawa H, Nadel JA, Goetzl EJ. Selective generation of leukotriene B4 by tracheal epithelial cells from dogs. Biochem Biophys Res Commun 1983;114(3):1071–1076.

    PubMed  CAS  Google Scholar 

  101. Hunter JA, Finkbeiner WE, Nadel JA, Goetzl EJ, Holtzman MJ. Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. Proc Natl Acad Sci USA 1985;82(14):4633–4637.

    PubMed  CAS  Google Scholar 

  102. Sigal E and Conrad DJ. Human lipoxygenase: A potential effector molecule for interleukin-4. In: Dahlen SE ed. Advances in Prostaglandins, Thromboxane and Leukotriene Research. Vol. 22. Raven, New York, 1994, pp. 309–316.

    Google Scholar 

  103. Dahlen, SE, Hansson G, Hedqvist P, Borck T, Granstrom E, Dahlen B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci USA 1983;80(6):1712–1716.

    PubMed  CAS  Google Scholar 

  104. Murray JJ, Tonnel AB, Brash AR, Rolberts LJD, Gosset P, Workman R, Capron A. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med 1986;315(13):800–804.

    PubMed  CAS  Google Scholar 

  105. Shannon VR, Chanez P, Bousquet J, Holtzman MJ. Histochemical evidence for induction of arachidonate 15-lipoxygenase in airway disease. Am Rev Respir Dis 1993;147(4):1024–1028.

    PubMed  CAS  Google Scholar 

  106. Kuitert LM, Newton R, Barnes NC, Adcock IM, Barnes PJ. Eicosanoid mediator expression in mononuclear and polymorphonuclear cells in normal subjects and patients with atopic asthma and cystic fibrosis. Thorax 1996;51(12):1223–1228.

    PubMed  CAS  Google Scholar 

  107. MacMillan DK, Hill E, Sala A, Sigal E, Shuman T, Henson PM, Murphy RC. Eosinophil 15-lipoxygenase is a leukotriene A4 synthase. J Biol Chem 1994; 269(43):26,663–26,668.

    CAS  Google Scholar 

  108. Copas JL, Borgeat P, Gardiner PJ. The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle. Prostaglandins Leukot Med 1982;8(2):105–114.

    PubMed  CAS  Google Scholar 

  109. Marom Z, Shelhamer JH, Sun, F, Kaliner M. Human airway monohydroxyeicosatetraenoic acid generation and mucus release. J Clin Invest 1983;72(1):122–127.

    PubMed  CAS  Google Scholar 

  110. Henke D, Danilowicz RM, Curtis JF, Boucher RC, Eling TE. Metabolism of arachidonic acid by human nasal and bronchial epithelial cells. Arch Biochem Biophys 1988;267(2):426–436.

    PubMed  CAS  Google Scholar 

  111. Lee TH, Crea AK, Gant V, Spur BW, Marron BE, Nicolaou KC, Reardon E. Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar ravage fluids obtained from patients with selected pulmonary diseases. Am Rev Respir Dis 1990;141(6):1453–1458.

    PubMed  CAS  Google Scholar 

  112. Levy BD, Romano M, Chapman HA, Reilly, JJ, Drazen J, Serhan CN. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-transeicosatetraenoic acid and lipoxins. J Clin Invest 1993;92(3):1572–1579.

    PubMed  CAS  Google Scholar 

  113. Lindgren JA, Edenius C, Kumlin M, Dahlen B, Anggard A. Conversion of leukotriene A4 to lipoxins by human nasal polyps and bronchial tissue. Adv Prostaglandin Thromboxane Leukot Res 1991;21A:89–92.

    PubMed  CAS  Google Scholar 

  114. Belkner J, Wiesner R, Rathman J, Barnett J, Sigal E, Kuhn H. Oxygenation of lipoproteins by mammalian lipoxygenases. Eur J Biochem 1993;213(1):251–261.

    PubMed  CAS  Google Scholar 

  115. Benz DJ, Mol M, Ezaki M, Mori-Ito N, Zelan I, Miyanohara A, Friedmann T. Enhanced levels of lipoperoxides in low density lipoprotein incubated with murine fibroblast expressing rich levels of human 15-lipoxygenase. J Biol Chem 1995;270(10):5191–5197.

    PubMed  CAS  Google Scholar 

  116. Kuhn H, Heydeck D, Hugou I, Gniwotta C. In vivo action of 15-lipoxygenase in early stages of human atherogenesis. J Clin Invest 1997;99(5):888–893.

    PubMed  CAS  Google Scholar 

  117. Yla-Herttuala S, Luoma J, Viita H, Hiltunen T, Sisto T, Nikkari T. Transfer of 15lipoxygenase gene into rabbit iliac arteries results in the appearance of oxidation-specific lipid-protein adducts characteristic of oxidized low density lipoprotein. J Clin Invest 1995;96(6):2692–2698.

    Google Scholar 

  118. Shen J, Herderick E, Cornhill JF, Zsigmond E, Kim HS, Kuhn H, Guevara NV. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J Clin Invest 1996;98(10):2201–2208.

    PubMed  CAS  Google Scholar 

  119. Winokur TS, Morrison AR. Regional synthesis of monohydroxy eicosanoids by the kidney. J Biol Chem 1981;256(20):10,221–10,223.

    CAS  Google Scholar 

  120. Sraer J, Rigaud M, Bens M, Rabinovitch H, Ardaillou R. Metabolism of arachidonic acid via the lipoxygenase pathway in human and murine glomeruli. J Biol Chem 1983;258(7):4325–4330.

    PubMed  CAS  Google Scholar 

  121. Antonipillai I, Nadler JL, Robin EC, Horton R. The inhibitory role of 12- and 15-lipoxygenase products on renin release. Hypertension 1987;10(1):61–66.

    PubMed  CAS  Google Scholar 

  122. Badr KF. 15-Lipoxygenase products as leukotriene antagonists: therapeutic potential in glomerulonephritis. Kidney Int Suppl 1992;38:S101–108.

    Google Scholar 

  123. Katoh T, Lakkis FG, Makita N, Badr KF. Co-regulated expression of glomerular 12/15 lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int 1994;46(2):341–349.

    PubMed  CAS  Google Scholar 

  124. Badr KF, Serhan CN, Nicolaou KC, Samuelsson B. The action of lipoxin-A on glomerular microcirculatory dynamics in the rat [published erratum appears in Biochem Biophys Res Commun 1987 Sep 30;147(3):1300]. Biochem. Biophys Res Commun 1987;145(1):408–414.

    PubMed  CAS  Google Scholar 

  125. Bailey JM, Bryant RW, Low CE, Pucillo MB, Vanderhoek JY. Regulation of T-lymphocyte mitogenesis by the leukocyte product 15-hydroxy-eicosatetraenoic acid (15-HETE). Cell Immunol 1982;67(1):112–120.

    PubMed  CAS  Google Scholar 

  126. Gualde N, Rabinovitch H, Fredon M, Rigaud M. Effects of 15-hydroperoxyeicosatetraenoic acid on human Iymphocyte sheep erythrocyte rosette formation and response to concanavalin A associated with HLA system. Eur J Immunol 1982;12(9):773–777.

    PubMed  CAS  Google Scholar 

  127. Gualde N, Chable-Rabinovitch H, Motta C, Durand J, Beneytout JL, Rigaud M. Hydroperoxyeicosatetraenoic acids. Potent inhibitors of Iymphocyte responses. Biochim Biophys Acta 1983;750(3):429–433.

    PubMed  CAS  Google Scholar 

  128. Petrich K, Ludwig P, Kuhn H, Schevve T. The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15S)-hydroxy-(5Z, 8Z, 11Z, 13E)-eicosatetraenoic acid: structure-activity relationship and mechanism of action. Biochem J 1996;314(Pt 3): 911–916.

    PubMed  CAS  Google Scholar 

  129. Palmer RM, Stepney RJ, Higgs GA, Eakins KE. Chemokinetic activity of arachidonic and lipoxygenase products on leuocyctes of different species. Prostaglandins 1980;20(2):411–418.

    PubMed  CAS  Google Scholar 

  130. Vanderhoek JY, Bryant RW, Bailey JM. 15-hydroxy-5,8,11,13-eicosatetraenoic acid: A potent and selective inhibitor of platelet lipoxygenase. J Biol Chem 1980;255(13):5996–5998.

    PubMed  CAS  Google Scholar 

  131. Vericel E, Lagarde M. 15-Hydroperoxyeicosatetraenoic acid inhibits human platelet aggregation. Lipids 1980;15(6):472–474.

    PubMed  CAS  Google Scholar 

  132. Yamazaki T, Higuchi K, Kominami S, Takemori S 15-lipoxygenase metabolite(s) of arachidonic acid mediates adrenocorticotropin action in bovine adrenal steroidogenesis. Endocrinology 1996;137(7):2670–2675.

    PubMed  CAS  Google Scholar 

  133. Van Diest MJ, Verbeuren TJ, Herman AG. Cyclo-oxygenase blockers influence the effects of 15-lipoxygenase metabolites of arachidonic acid in isolated canine blood vessels. Prostaglandins 1986;32(1):97–100.

    PubMed  Google Scholar 

  134. Aharony, D, Smith JB, Smith EFD, Lefer AM. Effects of arachidonic acid hydroperoxides on vascular and non-vascular smooth muscle. Prostaglandins Med 1981;7(6):527–535.

    PubMed  CAS  Google Scholar 

  135. Nathan MH, Pek SB. Lipoxygenase generated icosanoids inhibit glucose-induced insulin release from rat islets. Prostaglandins Leukot Essent Fatty Acids 1990;40(1):21–25.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Conrad, D.J. The arachidonate 12/15 lipoxygenases. Clinic Rev Allerg Immunol 17, 71–89 (1999). https://doi.org/10.1007/BF02737598

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02737598

Keywords

Navigation