Genetic regulation of leukotriene production and activity

  • I. Sayers
  • A. P. Sampson
Part of the Progress in Inflammation Research book series (PIR)


Leukotrienes (LTs) have been identified as critical mediators of airway narrowing and eosinophilia in bronchial asthma. They potently contract human bronchial smooth muscle, promote mucus secretion and impair muciliary clearance, increase vascular permeability leading to airway oedema, and, specifically, chemoattract human eosinophils in vitro and in vivo. In view of the importance of these lipid mediators in the pathogenesis of asthma, substantial effort has been directed at elucidating the mechanisms that regulate their production by the 5-lipoxygenase pathway and those that mediate their effects [1]. This work led directly to the development of a series of LT modifier drugs that show clinical efficiency in asthma and represent the first new form of asthma treatment in 25 years [2, 3].


Respir Crit Human Eosinophil Human Lung Mast Cell LTB4 Receptor LTA4 Hydrolase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Holgate S, Dahlen S-E (eds) (1997) SRS-A to leukotrienes: The dawning of a new treatment. Blackwell Science, Oxford, UK, 336Google Scholar
  2. 2.
    Drazen JM, Israel E, O’Byrne PM (1999) Treatment of asthma with drugs modifying the leukotriene pathway [published errata appear in N Engl J Med (1999) 340 (8): 663 and 341 (21): 1632]. N Engl J Med 340: 197–206PubMedGoogle Scholar
  3. 3.
    Holgate ST, Sampson AP (2000) Antileukotriene therapy. Future directions. Am J Respir Crit Care Med 161: S147–153Google Scholar
  4. 4.
    Samuelsson B (1987) An elucidation of the arachidonic acid cascade. Discovery of prostaglandins, thromboxane and leukotrienes. Drugs 33 (Suppl 1): 2–9PubMedGoogle Scholar
  5. 5.
    MacGlashan DW, Jr., Schleimer RP, Peters SP, Schulman ES, Adams GKd, Newball HH, Lichtenstein LM (1982) Generation of leukotrienes by purified human lung mast cells. J Clin Invest 70: 747–751PubMedGoogle Scholar
  6. 6.
    Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA (1983) Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: Predominant production of leukotriene c4. Proc Natl Acad Sci USA 80: 7626–7630PubMedGoogle Scholar
  7. 7.
    Williams JD, Czop JK, Austen KF (1984) Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators. J Immunol 132: 3034–3040PubMedGoogle Scholar
  8. 8.
    Dahlen SE, Hedqvist P, Hammarstrom S, Samuelsson B (1980) Leukotrienes are potent constrictors of human bronchi. Nature 288: 484–486PubMedGoogle Scholar
  9. 9.
    Weiss JW, Drazen JM, McFadden ER Jr, Weller P, Corey EJ, Lewis RA, Austen KF (1983) Airway constriction in normal humans produced by inhalation of leukotriene d. Potency, time course, and effect of aspirin therapy. Jama 249: 2814–2817PubMedGoogle Scholar
  10. 10.
    Barnes NC, Piper PJ, Costello JF (1984) Comparative effects of inhaled leukotriene c4, leukotriene d4, and histamine in normal human subjects. Thorax 39: 500–504PubMedGoogle Scholar
  11. 11.
    Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner M (1982) Slow-reacting substances, leukotrienes c4 and d4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis 126: 449–451PubMedGoogle Scholar
  12. 12.
    Arm JP, Lee TH (1993) Sulphidopeptide leukotrienes in asthma [editorial]. Clin Sci (Colch) 84: 501–510Google Scholar
  13. 13.
    Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P et al (1990) Eosinophilic inflammation in asthma. N Engl J Med 323: 1033–1039PubMedGoogle Scholar
  14. 14.
    Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH (1993) Leukotriene e4 and granulocytic infiltration into asthmatic airways. Lancet 341: 989–990PubMedGoogle Scholar
  15. 15.
    Spada CS, Nieves AL, Krauss AH, Woodward DF (1994) Comparison of leukotriene b4 and d4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 55: 183–191Google Scholar
  16. 16.
    Okubo T, Takahashi H, Sumitomo M, Shindoh K, Suzuki S (1987) Plasma levels of leukotrienes c4 and d4 during wheezing attack in asthmatic patients. Int Arch Allergy Appl Immunol 84: 149–155PubMedGoogle Scholar
  17. 17.
    Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY (1990) Elevated levels of leukotriene c4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis 142: 112–119PubMedGoogle Scholar
  18. 18.
    Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW, Dollery CT (1989) Urinary leukotriene e4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet 1: 584–588PubMedGoogle Scholar
  19. 19.
    Kumlin M, Dahlen B, Bjorck T, Zetterstrom O, Granstrom E, Dahlen SE (1992) Urinary excretion of leukotriene e4 and 11-dehydro-thromboxane b2 in response to bronchial provocations with allergen, aspirin, leukotriene d4, and histamine in asthmatics. Am Rev Respir Dis 146: 96–103PubMedGoogle Scholar
  20. 20.
    Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL (1988) Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis 137: 847–854PubMedGoogle Scholar
  21. 21.
    Picado C, Ramis I, Rosello J, Prat J, Bulbena O, Plaza V, Montserrat JM, Gelpi E (1992) Release of peptide leukotriene into nasal secretions after local instillation of aspirin in aspirin-sensitive asthmatic patients. Am Rev Respir Dis 145: 65–69PubMedGoogle Scholar
  22. 22.
    Creticos PS, Peters SP, Adkinson NF, Jr., Naclerio RM, Hayes EC, Norman PS, Lichtenstein LM (1984) Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med 310: 1626–1630PubMedGoogle Scholar
  23. 23.
    Hoover RL, Karnovsky MJ, Austen KF, Corey EJ, Lewis RA (1984) Leukotriene b4 action on endothelium mediates augmented neutrophil/endothelial adhesion. Proc Natl Acad Sci USA 81: 2191–2193PubMedGoogle Scholar
  24. 24.
    Yamaoka KA, Kolb JP (1993) Leukotriene b4 induces interleukin 5 generation from human t lymphocytes. Eur J Immunol 23: 2392–2398PubMedGoogle Scholar
  25. 25.
    Brach MA, de Vos S, Arnold C, Gruss HJ, Mertelsmann R, Herrmann F (1992) Leukotriene b4 transcriptionally activates interleukin-6 expression involving nk-chi b and nf-i16. Eur J Immunol 22: 2705–2711PubMedGoogle Scholar
  26. 26.
    Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The pparalpha-leukotriene b4 pathway to inflammation control. Nature 384: 39–43PubMedGoogle Scholar
  27. 27.
    Aoki Y, Qiu D, Zhao GH, Kao PN (1998) Leukotriene b4 mediates histamine induction of nf-kappab and it-8 in human bronchial epithelial cells. Am J Physiol 274: L1030–1039PubMedGoogle Scholar
  28. 28.
    Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST et al (1998) Overexpression of leukotriene c4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 101: 834–846PubMedGoogle Scholar
  29. 29.
    Dahlen SE, Haeggstrom JZ, Samuelsson B, Rabe KF, Leff AR (2000) Leukotrienes as targets for the treatment of asthma and other diseases: Current basic and clinical research. Am J Crit Care Med 161 (Suppl): S1–153Google Scholar
  30. 30.
    Coleman RA, Eglen RM, Jones RL, Narumiya S, Shimizu T, Smith WL, Dahlen SE, Drazen JM, Gardiner PJ, Jackson WT et al (1995) Prostanoid and leukotriene receptors: A progress report from the iuphar working parties on classification and nomenclature. Adv Prostaglandin Thromboxane Leukot Res 23: 283–285PubMedGoogle Scholar
  31. 31.
    Metters KM (1995) Leukotriene receptors. J Lipid Mediat Cell Signal 12: 413–427PubMedGoogle Scholar
  32. 32.
    Votta B, Mong S (1990) Transition of affinity states for leukotriene b4 receptors in sheep lung membranes. Biochem J 265: 841–847PubMedGoogle Scholar
  33. 33.
    Owman C, Sabirsh A, Garzino-Demo A, Cocchi F (2000) Cloning of a novel chemoattractant receptor activated by leukotriene b4 and used by human immunodeficiency virus type 1 to infect cd4-positive immune cells. A therapeutic connection to asthma? Am J Respir Crit Care Med 161: S56–61PubMedGoogle Scholar
  34. 34.
    Labat C, Ortiz JL, Norel X, Gorenne I, Verley J, Abram TS, Cuthbert NJ, Tudhope SR, Norman P, Gardiner P et al (1992) A second cysteinyl leukotriene receptor in human lung. J Pharmacol Exp Ther 263: 800–805PubMedGoogle Scholar
  35. 35.
    Lynch KR, O’Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z et al (1999) Characterization of the human cysteinyl leukotriene cysltl receptor. Nature 399: 789–793PubMedGoogle Scholar
  36. 36.
    Sarau HM, Ames RS, Chambers J, Ellis C, Elshourbagy N, Foley JJ, Schmidt DB, Muccitelli RM, Jenkins O, Murdock PR et al (1999) Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol 56: 657–663PubMedGoogle Scholar
  37. 37.
    Heise CE, O’Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R et al (2000) Characterization of the human cysteinyl leukotriene 2 (CysLT2) receptor. J Biol Chem 275: 30531–30536PubMedGoogle Scholar
  38. 38.
    Sampson A, Holgate S (1998) Leukotriene modifiers in the treatment of asthma. Look promising across the board of asthma severity [editorial]. BMJ 316: 1257–1258PubMedGoogle Scholar
  39. 39.
    Holgate ST, Bradding P, Sampson AP (1996) Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy. J Allergy Clin Immunol 98: 1–13PubMedGoogle Scholar
  40. 40.
    Spector SL, Smith LJ, Glass M (1994) Effects of 6 weeks of therapy with oral doses of ici 204,219, a leukotriene d4 receptor antagonist, in subjects with bronchial asthma. Accolate asthma trialists group. Am J Respir Crit Care Med 150: 618–623PubMedGoogle Scholar
  41. 41.
    Evans DJ, Barnes PJ, Spaethe SM, van Alstyne EL, Mitchell MI, O’Connor BJ (1996) Effect of a leukotriene b4 receptor antagonist, ly293111, on allergen induced responses in asthma. Thorax 51: 1178–1184PubMedGoogle Scholar
  42. 42.
    Seymour M, Aberg D, Ruse G, Rak S, Holgate S, Sampson A (1998) Seasonal allergen exposure increases expression of leukotriene pathway enzymes and induces eosinophil influx in bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol 101: 711 (abstr)Google Scholar
  43. 43.
    Taniguchi N, Mita H, Saito H, Yui Y, Kajita T, Shida T (1985) Increased generation of leukotriene c4 from eosinophils in asthmatic patients. Allergy 40: 571–573PubMedGoogle Scholar
  44. 44.
    Bruijnzeel PL, Virchow JC, Jr., Rihs S, Walker C, Verhagen J (1993) Lack of increased numbers of low-density eosinophils in the circulation of asthmatic individuals. Clin Exp Allergy 23: 261–269PubMedGoogle Scholar
  45. 45.
    Laviolette M, Ferland C, Comtois JF, Champagne K, Bosse M, Boulet LP (1995) Blood eosinophil leukotriene c4 production in asthma of different severities. Eur Respir J 8: 1465–1472Google Scholar
  46. 46.
    Silberstein DS, Owen WF, Gasson JC, DiPersio JF, Golde DW, Bina JC, Soberman R, Austen KF, David JR (1986) Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocyte-macrophage colony-stimulating factor. J Immunol 137: 3290–3294PubMedGoogle Scholar
  47. 47.
    Rothenberg ME, Owen WF, Jr., Silberstein DS, Woods J, Soberman RJ, Austen KF, Stevens RL (1988) Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3. J Clin Invest 81: 1986–1992PubMedGoogle Scholar
  48. 48.
    Rothenberg ME, Petersen J, Stevens RL, Silberstein DS, McKenzie DT, Austen KF, Owen WF Jr (1989) I1–5-dependent conversion of normodense human eosinophils to the hypo-dense phenotype uses 3t3 fibroblasts for enhanced viability, accelerated hypodensity, and sustained antibody-dependent cytotoxicity. J Immunol 143: 2311–2316PubMedGoogle Scholar
  49. 49.
    Takafuji S, Bischoff SC, De Weck AL, Dahinden CA (1991) Il-3 and il-5 prime normal human eosinophils to produce leukotriene c4 in response to soluble agonists. J Immunol 147: 3855–3861PubMedGoogle Scholar
  50. 50.
    Boyce JA, Lam BK, Penrose JF, Friend DS, Parsons S, Owen WF, Austen KF (1996) Expression of ltc4 synthase during the development of eosinophils in vitro from cord blood progenitors. Blood 88: 4338–4347PubMedGoogle Scholar
  51. 51.
    DiPersio JF, Billing P, Williams R, Gasson JC (1988) Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene b4 synthesis. J Immunol 140: 4315–4322PubMedGoogle Scholar
  52. 52.
    McColl SR, DiPersio JF, Caon AC, Ho P, Naccache PH (1991) Involvement of tyrosine kinases in the activation of human peripheral blood neutrophils by granulocyte-macrophage colony-stimulating factor. Blood 78: 1842–1852PubMedGoogle Scholar
  53. 53.
    Pouliot M, McDonald PP, Khamzina L, Borgeat P, McColl SR (1994) Granulocyte-macrophage colony-stimulating factor enhances 5-lipoxygenase levels in human polymorphonuclear leukocytes. J Immunol 152: 851–858PubMedGoogle Scholar
  54. 54.
    Pouliot M, McDonald PP, Borgeat P, McColl SR (1994) Granulocyte/macrophage colony-stimulating factor stimulates the expression of the 5-lipoxygenase-activating protein (flap) in human neutrophils. J Exp Med 179: 1225–1232PubMedGoogle Scholar
  55. 55.
    Stankova J, Rola-Pleszczynski M, Dubois CM (1995) Granulocyte-macrophage colony-stimulating factor increases 5-lipoxygenase gene transcription and protein expression in human neutrophils. Blood 85: 3719–3726PubMedGoogle Scholar
  56. 56.
    Ring WL, Riddick CA, Baker JR, Munafo DA, Bigby TD (1996) Lymphocytes stimulate expression of 5-lipoxygenase and its activating protein in monocytes in vitro via granulocyte macrophage colony-stimulating factor and interleukin 3. J Clin Invest 97: 1293–1301PubMedGoogle Scholar
  57. 57.
    Ring WL, Riddick CA, Baker JR, Glass CK, Bigby TD (1997) Activated lymphocytes increase expression of 5-lipoxygenase and its activating protein in the-1 cells. Am J Physiol 273: C2057–2064PubMedGoogle Scholar
  58. 58.
    Bennett CF, Chiang MY, Monia BP, Crooke ST (1993) Regulation of 5-lipoxygenase and 5-lipoxygenase-activating protein expression in hl-60 cells. Biochem J 289: 33–39PubMedGoogle Scholar
  59. 59.
    Brungs M, Radmark O, Samuelsson B, Steinhilber D (1995) Sequential induction of 5lipoxygenase gene expression and activity in mono mac 6 cells by transforming growth factor beta and 1,25-dihydroxyvitamin d3. Proc Natl Acad Sci USA 92: 107–111PubMedGoogle Scholar
  60. 60.
    Nassar GM, Montero A, Fukunaga M, Badr KF (1997) Contrasting effects of proinflammatory and t-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes. Kidney Int 51: 1520–1528PubMedGoogle Scholar
  61. 61.
    Cowburn AS, Holgate ST, Sampson AP (1999) Il-5 increases expression of 5-lipoxygenase-activating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J Immunol 163: 456–465PubMedGoogle Scholar
  62. 62.
    Coffey MJ, Wilcoxen SE, Peters-Golden M (1994) Increases in 5-lipoxygenase activating protein expression account for enhanced capacity for 5-lipoxygenase metabolism that accompanies differentiation of peripheral blood monocytes into alveolar macrophages. Am J Respir Cell Mol Biol 11: 153–158PubMedGoogle Scholar
  63. 63.
    Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST (1994) Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: Evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 10: 471–480PubMedGoogle Scholar
  64. 64.
    Corrigan CJ, Haczku A, Gemou-Engesaeth V, Doi S, Kikuchi Y, Takatsu K, Durham SR, Kay AB (1993) Cd4 t-lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Effect of glucocorticoid therapy. Am Rev Respir Dis 147: 540–547Google Scholar
  65. 65.
    Brown PH, Crompton GK, Greening AP (1991) Proinflammatory cytokines in acute asthma. Lancet 338: 590–593PubMedGoogle Scholar
  66. 65a.
    Miyajima A, Mui AL, Ogorochi T, Sakamaki K (1993) Receptors for granulocyte colony-stimulating factor, interleukin 3, and interleukin 5. Blood 82 (7): 1960–1974PubMedGoogle Scholar
  67. 66.
    van der Bruggen T, Caldenhoven E, Kanters D, Coffer P, Raaijmakers JA, Lammers JW, Koenderman L (1995) Interleukin-5 signaling in human eosinophils involves jak2 tyrosine kinase and stat1 alpha. Blood 85: 1442–1448PubMedGoogle Scholar
  68. 67.
    van der Bruggen T, Kanters D, Tool AT, Raaijmakers JA, Lammers JW, Verhoeven AJ, Koenderman L (1998) Cytokine-induced protein tyrosine phosphorylation is essential for cytokine priming of human eosinophils. J Allergy Clin Immunol 101: 103–109PubMedGoogle Scholar
  69. 68.
    Woods JW, Evans JF, Ethier D, Scott S, Vickers PJ, Hearn L, Heibein JA, Charleson S, Singer, II (1993) 5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes. J Exp Med 178: 1935–1946PubMedGoogle Scholar
  70. 69.
    Brock TG, McNish RW, Bailie MB, Peters-Golden M (1997) Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence. J Biol Chem 272: 8276–8280PubMedGoogle Scholar
  71. 70.
    Brock TG, Anderson JA, Fries FP, Peters-Golden M, Sporn PH (1999) Decreased leukotriene c4 synthesis accompanies adherence-dependent nuclear import of 5-lipoxygenase in human blood eosinophils. J Immunol 162: 1669–1676PubMedGoogle Scholar
  72. 71.
    Lepley RA, Fitzpatrick FA (1994) 5-lipoxygenase contains a functional src homology 3-binding motif that interacts with the src homology 3 domain of grb2 and cytoskeletal proteins. J Biol Chem 269: 24163–24168PubMedGoogle Scholar
  73. 72.
    Lepley RA, Muskardin DT, Fitzpatrick FA (1996) Tyrosine kinase activity modulates catalysis and translocation of cellular 5-lipoxygenase. J Biol Chem 271: 6179–6184PubMedGoogle Scholar
  74. 73.
    Penrose JF, Spector J, Baldasaro M, Xu K, Boyce J, Arm JP, Austen KF, Lam BK (1996) Molecular cloning of the gene for human leukotriene c4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35. J Biol Chem 271: 11356–11361PubMedGoogle Scholar
  75. 74.
    Peers SH, Flower RJ (1990) The role of lipocortin in corticosteroid actions. Am Rev Respir Dis 141: S18–21PubMedGoogle Scholar
  76. 75.
    Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, Howarth PH, Holgate ST (1992) Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 145: 669–674PubMedGoogle Scholar
  77. 76.
    Riddick CA, Ring WL, Baker JR, Hodulik CR, Bigby TD (1997) Dexamethasone increases expression of 5-lipoxygenase and its activating protein in human monocytes and the-1 cells. Eur J Biochem 246: 112–118PubMedGoogle Scholar
  78. 77.
    Goppelt-Struebe M, Schaefer D, Habenicht AJ (1997) Differential regulation of cyclooxygenase-2 and 5-lipoxygenase-activating protein (flap) expression by glucocorticoids in monocytic cells. Br J Pharmacol 122: 619–624PubMedGoogle Scholar
  79. 78.
    Scoggan KA, Ford-Hutchinson AW, Nicholson DW (1995) Differential activation of leukotriene biosynthesis by granulocyte-macrophage colony-stimulating factor and interleukin-5 in an eosinophilic substrain of h1–60 cells. Blood 86: 3507–3516PubMedGoogle Scholar
  80. 79.
    Manso G, Baker AJ, Taylor IK, Fuller RW (1992) In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur Respir J 5: 712–716PubMedGoogle Scholar
  81. 80.
    Dworski R, Fitzgerald GA, Oates JA, Sheller JR (1994) Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 149: 953–959PubMedGoogle Scholar
  82. 81.
    Sayers I, Beghe B, Holloway J, Holgate S (2000) Genetics of asthma: What’s new? In: SHS Johnston (ed): Challenges in asthma. Blackwell Science, Oxford, UK, 138–168Google Scholar
  83. 82.
    Shamsuddin M, Chen E, Anderson J, Smith LJ (1997) Regulation of leukotriene and platelet-activating factor synthesis in human alveolar macrophages. J Lab Clin Med 130: 615–626PubMedGoogle Scholar
  84. 83.
    Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y et al (1997) Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390: 618–622PubMedGoogle Scholar
  85. 84.
    Peters-Golden M, McNish RW (1993) Redistribution of 5-lipoxygenase and cytosolic phospholipase a2 to the nuclear fraction upon macrophage activation. Biochem Biophys Res Commun 196: 147–153PubMedGoogle Scholar
  86. 85.
    Tay A, Simon JS, Squire J, Hamel K, Jacob HJ, Skorecki K (1995) Cytosolic phospholipase a2 gene in human and rat: Chromosomal localization and polymorphic markers. Genomics 26: 138–141PubMedGoogle Scholar
  87. 86.
    Sharp J, White D, G Chiou (1991) Molecular cloning and expression of human ca(2+)sensitive cytosolic phospholipase a2. J Biol Chem 266: 14850–14853PubMedGoogle Scholar
  88. 87.
    Wu T, Ikezono T, Angus W, Shelhamer J (1994) Characterisation of the promoter of the human 85 kda cytosolic phospholipase a2 gene. Nucleic Acid Research 22: 5093–5098Google Scholar
  89. 88.
    Miyashita A, Crystal RG, Hay JG (1995) Identification of a 27 bp 5’-flanking region element responsible for the low level constitutive expression of the human cytosolic phospholipase a2 gene. Nucleic Acids Res 23: 293–301PubMedGoogle Scholar
  90. 89.
    Song C, Chang XJ, Bean KM, Proia MS, Knopf JL, Kriz RW (1999) Molecular characterization of cytosolic phospholipase a2-beta. J Biol Chem 274: 17063–17067PubMedGoogle Scholar
  91. 90.
    Matsumoto T, Funk CD, Radmark O, Hoog JO, Jornvall H, Samuelsson B (1988) Molecular cloning and amino acid sequence of human 5-lipoxygenase [published erratum appears in Proc Natl Acad Sci USA (1988) 85 (10): 3406]. Proc Natl Acad Sci USA 85: 26–30PubMedGoogle Scholar
  92. 91.
    Steinhilber D, Brungs M, Radmark O, Samuelsson B (1995) Transforming growth factor-beta and 1,25-dihydroxyvitamin d3 induce 5-lipoxygenase activity during myeloid cell maturation. Adv Prostaglandin Thromboxane Leukot Res 23: 449–451PubMedGoogle Scholar
  93. 92.
    Coffey M, Peters-Golden M, Fantone JCd, Sporn PH (1992) Membrane association of active 5-lipoxygenase in resting cells. Evidence for novel regulation of the enzyme in the rat alveolar macrophage. J Biol Chem 267: 570–576PubMedGoogle Scholar
  94. 93.
    Koshino T, Takano S, Houjo T, Sano Y, Kudo K, Kihara H, Kitani S, Takaishi T, Hirai K, Ito K et al (1998) Expression of 5-lipoxygenase and 5-lipoxygenase-activating protein mrnas in the peripheral blood leukocytes of asthmatics. Biochem Biophys Res Commun 247: 510–513PubMedGoogle Scholar
  95. 94.
    Colamorea T, Di Paola R, Macchia F, Guerrese MC, Tursi A, Butterfield JH, Caiaffa MF, Haeggstrom JZ, Macchia L (1999) 5-lipoxygenase upregulation by dexamethasone in human mast cells. Biochem Biophys Res Commun 265: 617–624PubMedGoogle Scholar
  96. 95.
    Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B (1989) Characterization of the human 5-lipoxygenase gene. Proc Natl Acad Sci USA 86: 2587–2591PubMedGoogle Scholar
  97. 96.
    Hoshiko S, Radmark O, Samuelsson B (1990) Characterization of the human 5-lipoxygenase gene promoter. Proc Natl Acad Sci USA 87: 9073–9077PubMedGoogle Scholar
  98. 97.
    Boado RJ, Pardridge WM, Vinters HV, Black KL (1992) Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: Evidence for the expression of a multitranscript family. Proc Natl Acad Sci USA 89. 9044–9048PubMedGoogle Scholar
  99. 98.
    In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP et al (1997) Naturally occurring mutations in the human 5-lipoxy-genase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 99: 1130–1137PubMedGoogle Scholar
  100. 99.
    Silverman ES, Du J, De Sanctis GT, Radmark O, Samuelsson B, Drazen JM, Collins T (1998) Egr-1 and sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am J Respir Cell Mol Biol 19: 316–323PubMedGoogle Scholar
  101. 100.
    Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA et al (1999) Pharmacogenetic association between alox5 promoter genotype and the response to anti-asthma treatment. Nat Genet 22: 168–170PubMedGoogle Scholar
  102. 101.
    Silverman E, In KH, Yandava C, Drazen JM (1998) Pharmacogenetics of the 5-lipoxygenase pathway in asthma. Clin Exp Allergy 28 (Suppl 5): 164–170; discussion 171–163Google Scholar
  103. 102.
    Drazen JM, Silverman ES (1999) Genetic determinants of 5-lipoxy-genase transcription. Int Arch Allergy Immunol 118: 275–278PubMedGoogle Scholar
  104. 103.
    Silverman ES, Drazen JM (1999) The biology of 5-lipoxygenase: Function, structure, and regulatory mechanisms. Proc Assoc Am Physicians 111: 525–536PubMedGoogle Scholar
  105. 104.
    Silverman ES, Drazen JM (2000) Genetic variations in the 5-lipoxygenase core promoter. Description and functional implications. Am J Respir Crit Care Med 161: S77–80PubMedGoogle Scholar
  106. 105.
    Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK (1990) Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343: 282–284PubMedGoogle Scholar
  107. 106.
    Kennedy B, Diehl R, Boie Y, Adam M, Dixon R (1991) Gene characterisation and promoter analysis of the human 5-lipoxygenase-activating protein (flap). J Biol Chem 266: 8511–8516PubMedGoogle Scholar
  108. 107.
    Yandava CN, Kennedy BP, Pillari A, Duncan AM, Drazen JM (1999) Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (alox5ap) to chromosome 13q12. Genomics 56: 131–133PubMedGoogle Scholar
  109. 108.
    Yoshida S, Penrose J, Stevenson D, Shikanani T, Asano K, Yandava C, Drazen J (2000) Polymorphism with genes in cysteinyl leukotriene synthesis pathway in aspirin-intolerant asthma. Am J Respir Crit Care Med 161 (3): A602 (abstract)Google Scholar
  110. 109.
    Lam BK, Penrose JF, Freeman GJ, Austen KF (1994) Expression cloning of a cdna for human leukotriene c4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene a4. Proc Natl Acad Sci USA 91: 7663–7667PubMedGoogle Scholar
  111. 110.
    Welsch DJ, Creely DP, Hauser SD, Mathis KJ, Krivi GG, Isakson PC (1994) Molecular cloning and expression of human leukotriene-c4 synthase. Proc Natl Acad Sci USA 91: 9745–9749PubMedGoogle Scholar
  112. 111.
    Scoggan KA, Jakobsson PJ, Ford-Hutchinson AW (1997) Production of leukotriene c4 in different human tissues is attributable to distinct membrane bound biosynthetic enzymes. J Biol Chem 272: 10182–10187PubMedGoogle Scholar
  113. 112.
    Bigby TD, Hodulik CR, Arden KC, Fu L (1996) Molecular cloning of the human leukotriene c4 synthase gene and assignment to chromosome 5q35. Mol Med 2: 637–646PubMedGoogle Scholar
  114. 113.
    Zhao JL, Austen KF, Lam BK (2000) Cell-specific transcription of leukotriene c(4) synthase involves a kruppel-like transcription factor and sp1. J Biol Chem 275: 8903–8910PubMedGoogle Scholar
  115. 114.
    Zaitsu M, Hamasaki Y, Yamamoto S, Kita M, Hayasaki R, Muro E, Kobayashi I, Matsuo M, Ichimaru T, Miyazaki S (1998) Effect of dexamethasone on leukotriene synthesis in dmso-stimulated h1–60 cells. Prostaglandins Leukot Essent Fatty Acids 59: 385–393PubMedGoogle Scholar
  116. 115.
    Riddick CA, Serio KJ, Hodulik CR, Ring WL, Regan MS, Bigby TD (1999) Tgf-beta increases leukotriene c4 synthase expression in the monocyte-like cell line, the-1. J Immunol 162: 1101–1107PubMedGoogle Scholar
  117. 116.
    Shimada K, Navarro J, Goeger DE, Mustafa SB, Weigel PH, Weinman SA (1998) Expression and regulation of leukotriene-synthesis enzymes in rat liver cells. Hepatology 28: 1275–1281PubMedGoogle Scholar
  118. 117.
    Sanak M, Simon HU, Szczeklik A (1997) Leukotriene c4 synthase promoter polymorphism and risk of aspirin-induced asthma [letter]. Lancet 350: 1599–1600PubMedGoogle Scholar
  119. 118.
    Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A (2000) Enhanced expression of the leukotriene c4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 23: 290–296PubMedGoogle Scholar
  120. 119.
    Szczeklik A, Stevenson DD (1999) Aspirin-induced asthma: Advances in pathogenesis and management. J Allergy Clin Immunol 104: 5–13PubMedGoogle Scholar
  121. 120.
    Sampson A, Siddiqui S, Cowburn A, Buchanan D, Howarth P, Holgate S, Holloway J, Sayers I (2000) Variant ltc4 synthase allele modifies cysteinyl-leukotriene synthesis in eosinophils and predicts clinical response to zafarlukast. Thorax 55 (Suppl 2): S28–S31PubMedGoogle Scholar
  122. 121.
    Minami M, Ohno S, Kawasaki H, Radmark O, Samuelsson B, Jornvall H, Shimizu T, Seyama Y, Suzuki K (1987) Molecular cloning of a cdna coding for human leukotriene a4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis. J Biol Chem 262: 13873–13876PubMedGoogle Scholar
  123. 122.
    Funk CD, Radmark O, Fu JY, Matsumoto T, Jornvall H, Shimizu T, Samuelsson B (1987) Molecular cloning and amino acid sequence of leukotriene a4 hydrolase. Proc Natl Acad Sci USA 84: 6677–6681PubMedGoogle Scholar
  124. 123.
    Mancini JA, Evans JF (1995) Cloning and characterization of the human leukotriene a4 hydrolase gene. Eur J Biochem 231: 65–71PubMedGoogle Scholar
  125. 124.
    Jendraschak E, Kaminski WE, Kiefl R, von Schacky C (1996) The human leukotriene a4 hydrolase gene is expressed in two alternatively spliced mrna forms. Biochem J 314: 733–737PubMedGoogle Scholar
  126. 125.
    Bulle F, Maffei MG, Siegrist S, Pawlak A, Passage E, Chobert MN, Laperche Y, Guellaen G (1987) Assignment of the human gamma-glutamyl transferase gene to the long arm of chromosome 22. Hum Genet 76: 283–286PubMedGoogle Scholar
  127. 126.
    Sakamuro D, Yamazoe M, Matsuda Y, Kangawa K, Taniguchi N, Matsuo H, Yoshikawa H, Ogasawara N (1988) The primary structure of human gamma-glutamyl transpeptidase. Gene 73: 1–9PubMedGoogle Scholar
  128. 127.
    Pawlak A, Wu SJ, Bulle F, Suzuki A, Chikhi N, Ferry N, Baik JH, Siegrist S, Guellaen G (1989) Different gamma-glutamyl transpeptidase mrnas are expressed in human liver and kidney. Biochem Biophys Res Commun 164: 912–918PubMedGoogle Scholar
  129. 128.
    Kozak EM, Tate SS (1982) Glutathione-degrading enzymes of microvillus membranes. J Biol Chem 257: 6322–6327PubMedGoogle Scholar
  130. 129.
    Adachi H, Tawaragi Y, Inuzuka C, Kubota I, Tsujimoto M, Nishihara T, Nakazato H (1990) Primary structure of human microsomal dipeptidase deduced from molecular cloning. J Biol Chem 265: 3992–3995PubMedGoogle Scholar
  131. 130.
    Carter BZ, Wiseman AL, Orkiszewski R, Ballard KD, Ou CN, Lieberman MW (1997) Metabolism of leukotriene c4 in gamma-glutamyl transpeptidase-deficient mice. J Biol Chem 272: 12305–12310PubMedGoogle Scholar
  132. 131.
    Habib GM, Shi ZZ, Cuevas AA, Guo Q, Matzuk MM, Lieberman MW (1998) Leukotriene d4 and cystinyl-bis-glycine metabolism in membrane-bound dipeptidasedeficient mice. Proc Natl Acad Sci USA 95: 4859–4863PubMedGoogle Scholar
  133. 132.
    Owman C, Nilsson C, Lolait SJ (1996) Cloning of cdna encoding a putative chemoattractant receptor. Genomics 37: 187–194PubMedGoogle Scholar
  134. 133.
    Akbar GKM, Dasari VR, Webb TE, Ayyanathan K, Pillarisetti K, Sandhu AK, Athwal RS, Daniel JL, Ashby B, Barnard EA et al (1996) Molecular cloning of a novel p2 purinoceptor from human erythroleukemia cells. J Biol Chem 271: 18363–18367PubMedGoogle Scholar
  135. 134.
    Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T (1997) A g-protein-coupled receptor for leukotriene b4 that mediates chemotaxis. Nature 387: 620–624PubMedGoogle Scholar
  136. 135.
    Yokomizo T, Masuda K, Kato K, Toda A, Izumi T, Shimizu T (2000) Leukotriene b4 receptor. Cloning and intracellular signaling. Am J Respir Crit Care Med 161: S51–55PubMedGoogle Scholar
  137. 136.
    Pulleyn L, Adcock I, Barnes P (2000) A screen of the cysltl receptor gene for polymorphisms associated with asthma severity. American Thoracic Society, Toronto, meeting abstractGoogle Scholar
  138. 137.
    Bolk S, Lilly C, Yandava C, Green M, Lander E, Daly M, Evans J, Metzker M, Drazen J (2000) Naturally occuring sequence variants in the cysltl receptor. American Thoracic Society, Toronto, meeting abstractGoogle Scholar
  139. 138.
    Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW (1998) Effects of ltd4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: Differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 19: 453–461PubMedGoogle Scholar
  140. 139.
    Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX, Seidenberg BC, Reiss TF (1999) Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/beclomethasone study group. Ann Intern Med 130: 487–495PubMedGoogle Scholar
  141. 140.
    Hasday JD, Meltzer SS, Moore WC, Wisniewski P, Hebel JR, Lanni C, Dube LM, Bleecker ER (2000) Anti-inflammatory effects of zileuton in a subpopulation of allergic asthmatics. Am J Respir Crit Care Med 161: 1229–1236PubMedGoogle Scholar
  142. 141.
    Goulet JL, Byrum RS, Key ML, Nguyen M, Wagoner VA, Koller BH (2000) Genetic factors determine the contribution of leukotrienes to acute inflammatory responses. J Immunol 164: 4899–4907PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  • I. Sayers
    • 1
  • A. P. Sampson
    • 2
  1. 1.Human GeneticsSouthampton General HospitalSouthamptonUK
  2. 2.Respiratory Cell & Molecular Biology Research DivisionSouthampton General HospitalSouthamptonUK

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