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. 1993 Sep;92(3):1572–1579. doi: 10.1172/JCI116738

Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins.

B D Levy 1, M Romano 1, H A Chapman 1, J J Reilly 1, J Drazen 1, C N Serhan 1
PMCID: PMC288306  PMID: 8376607

Abstract

Eicosanoids derived from lipoxygenase (LO)-catalyzed reactions play important roles in pulmonary inflammation. Here, we examined formation of LO-derived products by human alveolar macrophages (HAM). HAM converted [1-14C]-arachidonic acid to a product carrying 14C-radiolabel that was identified as 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15-HETE) by physical methods. 15-LO mRNA was demonstrated in HAM by reverse transcription-polymerase chain reaction. Incubation of HAM for 3 d with interleukin 4(IL-4) before exposure to [1-14C]arachidonic acid led to both increased mRNA for 15-LO and a 4-fold increase in 15-HETE formation. In contrast, 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid generation was not significantly altered by prior exposure to IL-4. Additionally, lipoxins (LXA4 and LXB4) were detected from endogenous substrate, albeit in lower levels than leukotriene B4 (LTB4), in electrochemical detection/high performance liquid chromatography profiles from HAM incubated in the presence and absence of the chemotactic peptide (FMLP) or the calcium ionophore (A23187). Exposure of HAM to leukotriene A4 (LTA4) resulted in a 2-fold increase in LXA4 and 10-fold increase in LXB4. These results demonstrate the presence of 15-LO mRNA and enzyme activity in HAM and the production of LXA4 and LXB4 by these cells. Along with 5-LO-derived products, the biosynthesis of 15-LO-derived eicosanoids by HAM may also be relevant in modulating inflammatory responses in the lung.

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Selected References

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  1. Brezinski M. E., Serhan C. N. Selective incorporation of (15S)-hydroxyeicosatetraenoic acid in phosphatidylinositol of human neutrophils: agonist-induced deacylation and transformation of stored hydroxyeicosanoids. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6248–6252. doi: 10.1073/pnas.87.16.6248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chavis C., Godard P., Crastes de Paulet A., Damon M. Formation of lipoxins and leukotrienes by human alveolar macrophages incubated with 15(S)-HETE: a model for cellular cooperation between macrophages and airway epithelial cells. Eicosanoids. 1992;5(3-4):203–211. [PubMed] [Google Scholar]
  3. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  4. Christie P. E., Spur B. W., Lee T. H. The effects of lipoxin A4 on airway responses in asthmatic subjects. Am Rev Respir Dis. 1992 Jun;145(6):1281–1284. doi: 10.1164/ajrccm/145.6.1281. [DOI] [PubMed] [Google Scholar]
  5. Conrad D. J., Kuhn H., Mulkins M., Highland E., Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):217–221. doi: 10.1073/pnas.89.1.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dahinden C. A., Clancy R. M., Gross M., Chiller J. M., Hugli T. E. Leukotriene C4 production by murine mast cells: evidence of a role for extracellular leukotriene A4. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6632–6636. doi: 10.1073/pnas.82.19.6632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dahlén S. E., Kumlin M., Björck T., Raud J., Wikström E., Hedqvist P. Lipoxins and other lipoxygenase products with relevance to inflammatory reactions in the lung. Ann N Y Acad Sci. 1991;629:262–273. doi: 10.1111/j.1749-6632.1991.tb37982.x. [DOI] [PubMed] [Google Scholar]
  8. Edenius C., Kumlin M., Björk T., Anggård A., Lindgren J. A. Lipoxin formation in human nasal polyps and bronchial tissue. FEBS Lett. 1990 Oct 15;272(1-2):25–28. doi: 10.1016/0014-5793(90)80440-t. [DOI] [PubMed] [Google Scholar]
  9. Fels A. O., Cohn Z. A. The alveolar macrophage. J Appl Physiol (1985) 1986 Feb;60(2):353–369. doi: 10.1152/jappl.1986.60.2.353. [DOI] [PubMed] [Google Scholar]
  10. Fels A. O., Pawlowski N. A., Cramer E. B., King T. K., Cohn Z. A., Scott W. A. Human alveolar macrophages produce leukotriene B4. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7866–7870. doi: 10.1073/pnas.79.24.7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fiore S., Serhan C. N. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J Exp Med. 1990 Nov 1;172(5):1451–1457. doi: 10.1084/jem.172.5.1451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Funk C. D., FitzGerald G. A. Eicosanoid forming enzyme mRNA in human tissues. Analysis by quantitative polymerase chain reaction. J Biol Chem. 1991 Jul 5;266(19):12508–12513. [PubMed] [Google Scholar]
  13. Hamberg M., Hedqvist P., Rådegran K. Identification of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) as a major metabolite of arachidonic acid in human lung. Acta Physiol Scand. 1980 Oct;110(2):219–221. doi: 10.1111/j.1748-1716.1980.tb06656.x. [DOI] [PubMed] [Google Scholar]
  14. Hedqvist P., Raud J., Palmertz U., Haeggström J., Nicolaou K. C., Dahlén S. E. Lipoxin A4 inhibits leukotriene B4-induced inflammation in the hamster cheek pouch. Acta Physiol Scand. 1989 Dec;137(4):571–572. doi: 10.1111/j.1748-1716.1989.tb08805.x. [DOI] [PubMed] [Google Scholar]
  15. Herrmann T., Steinhilber D., Knospe J., Roth H. J. Determination of picogram amounts of lipoxin A4 and lipoxin B4 by high-performance liquid chromatography with electrochemical detection. J Chromatogr. 1988 Jul 15;428(2):237–245. doi: 10.1016/s0378-4347(00)83914-6. [DOI] [PubMed] [Google Scholar]
  16. Holtzman M. J., Turk J., Shornick L. P. Identification of a pharmacologically distinct prostaglandin H synthase in cultured epithelial cells. J Biol Chem. 1992 Oct 25;267(30):21438–21445. [PubMed] [Google Scholar]
  17. Kumlin M., Hamberg M., Granström E., Björck T., Dahlén B., Matsuda H., Zetterström O., Dahlén S. E. 15(S)-hydroxyeicosatetraenoic acid is the major arachidonic acid metabolite in human bronchi: association with airway epithelium. Arch Biochem Biophys. 1990 Nov 1;282(2):254–262. doi: 10.1016/0003-9861(90)90114-e. [DOI] [PubMed] [Google Scholar]
  18. Laviolette M., Coulombe R., Picard S., Braquet P., Borgeat P. Decreased leukotriene B4 synthesis in smokers' alveolar macrophages in vitro. J Clin Invest. 1986 Jan;77(1):54–60. doi: 10.1172/JCI112301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lee T. H., Crea A. E., Gant V., Spur B. W., Marron B. E., Nicolaou K. C., Reardon E., Brezinski M., Serhan C. N. Identification of lipoxin A4 and its relationship to the sulfidopeptide leukotrienes C4, D4, and E4 in the bronchoalveolar lavage fluids obtained from patients with selected pulmonary diseases. Am Rev Respir Dis. 1990 Jun;141(6):1453–1458. doi: 10.1164/ajrccm/141.6.1453. [DOI] [PubMed] [Google Scholar]
  20. Lee T. H., Horton C. E., Kyan-Aung U., Haskard D., Crea A. E., Spur B. W. Lipoxin A4 and lipoxin B4 inhibit chemotactic responses of human neutrophils stimulated by leukotriene B4 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Clin Sci (Lond) 1989 Aug;77(2):195–203. doi: 10.1042/cs0770195. [DOI] [PubMed] [Google Scholar]
  21. Meade E. A., Smith W. L., DeWitt D. L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993 Mar 25;268(9):6610–6614. [PubMed] [Google Scholar]
  22. Munger J. S., Shi G. P., Mark E. A., Chin D. T., Gerard C., Chapman H. A. A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. J Biol Chem. 1991 Oct 5;266(28):18832–18838. [PubMed] [Google Scholar]
  23. Murray J. J., Tonnel A. B., Brash A. R., Roberts L. J., 2nd, Gosset P., Workman R., Capron A., Oates J. A. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med. 1986 Sep 25;315(13):800–804. doi: 10.1056/NEJM198609253151304. [DOI] [PubMed] [Google Scholar]
  24. Park L. S., Friend D., Sassenfeld H. M., Urdal D. L. Characterization of the human B cell stimulatory factor 1 receptor. J Exp Med. 1987 Aug 1;166(2):476–488. doi: 10.1084/jem.166.2.476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pettitt T. R., Rowley A. F., Barrow S. E., Mallet A. I., Secombes C. J. Synthesis of lipoxins and other lipoxygenase products by macrophages from the rainbow trout, Oncorhynchus mykiss. J Biol Chem. 1991 May 15;266(14):8720–8726. [PubMed] [Google Scholar]
  26. Ponte P., Ng S. Y., Engel J., Gunning P., Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984 Feb 10;12(3):1687–1696. doi: 10.1093/nar/12.3.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  28. Romano M., Serhan C. N. Lipoxin generation by permeabilized human platelets. Biochemistry. 1992 Sep 8;31(35):8269–8277. doi: 10.1021/bi00150a021. [DOI] [PubMed] [Google Scholar]
  29. Serhan C. N. Lipoxins: eicosanoids carrying intra- and intercellular messages. J Bioenerg Biomembr. 1991 Feb;23(1):105–122. doi: 10.1007/BF00768841. [DOI] [PubMed] [Google Scholar]
  30. Serhan C. N., Sheppard K. A., Fiore S. Lipoxin formation: evaluation of the role and actions of leukotriene A4. Adv Prostaglandin Thromboxane Leukot Res. 1990;20:54–62. [PubMed] [Google Scholar]
  31. Sigal E., Craik C. S., Highland E., Grunberger D., Costello L. L., Dixon R. A., Nadel J. A. Molecular cloning and primary structure of human 15-lipoxygenase. Biochem Biophys Res Commun. 1988 Dec 15;157(2):457–464. doi: 10.1016/s0006-291x(88)80271-7. [DOI] [PubMed] [Google Scholar]
  32. Spector A. A., Gordon J. A., Moore S. A. Hydroxyeicosatetraenoic acids (HETEs). Prog Lipid Res. 1988;27(4):271–323. doi: 10.1016/0163-7827(88)90009-4. [DOI] [PubMed] [Google Scholar]
  33. Stenke L., Mansour M., Edenius C., Reizenstein P., Lindgren J. A. Formation and proliferative effects of lipoxins in human bone marrow. Biochem Biophys Res Commun. 1991 Oct 15;180(1):255–261. doi: 10.1016/s0006-291x(05)81285-9. [DOI] [PubMed] [Google Scholar]
  34. Walden T. L., Jr Radioprotection of mouse hematopoietic stem cells by leukotriene A4 and lipoxin B4. J Radiat Res. 1988 Dec;29(4):255–260. doi: 10.1269/jrr.29.255. [DOI] [PubMed] [Google Scholar]
  35. Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta. 1992 Oct 30;1128(2-3):117–131. doi: 10.1016/0005-2760(92)90297-9. [DOI] [PubMed] [Google Scholar]

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