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Conversion of Leukotriene D4 to Leukotriene E4 by a Dipeptidase Released from the Specific Granule of Human Polymorphonuclear Leucocytes

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Conversion of Leukotriene D4 to Leukotriene E4 by a Dipeptidase Released from the Specific Granule of Human Polymorphonuclear Leucocytes Immunology 1983 48 27 Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes C. W. LEE, R. A. LEWIS, E. J. COREY & K. F. AUSTEN Department ofMedicine, Harvard Medical School and the Department ofRheumatology andImmunology, Brigham and Women's Hospital, Boston, Massachusetts and Department of Chemistry, Harvard University, Cambridge, Massachusetts, U.S.A. Acceptedfor publication 15 June 1982 Summary. Leukotriene D4 (LTD4), the most active activity, termed LTD4 dipeptidase, to be localized only spasmogenic leukotriene constituent ofthe slow react- in the granule fraction. There was a time- and ing substance of anaphylaxis, was converted by sus- calcium-dependent extracellular release of LTD4 pended human polymorphonuclear leucocytes dipeptidase in association with lysozyme (r =097, (PMNs) to a single, less polar metabolite which was n= 16, P<0 001), a constituent of both specific and not further catabolized. This product was identified as azurophilic granules, in the absence of release of leukotriene E4 (LTE4) by its retention time during cytoplasmic lactate dehydrogenase (LDH) and of reverse phase-high performance liquid chromato- f,-glucuronidase from the azurophilic granule. Phor- graphy (RP-HPLC) and subsequent bioassay on the bol myristate acetate (PMA), which selectively induces guinea-pig ileum. LTD4 with a retention time of secretion of specific granules, released lysozyme and 21 + 1 6 min (mean + SD) and a contractile activity of the LTD4 dipeptidase in a constant dose-dependent 5-0 + 0 4 u./pmol (mean + SD) was quantitatively con- manner from PMNs (r=0-96, n=8, P<0 001). Cal- verted extracellularly by PMNs to LTE4 with a reten- cium ionophore A23187 at concentrations less than tion time of 26 + 1 8 min and a contractile activity of 10-7 M stimulated the parallel secretion of LTD4 1 2 + 0 3 u./pmol. Subcellular fractionations ofPMNs dipeptidase and lysozyme (r=0 91, n=9, P <0-005), revealed the recovered LTD4-to-LTE4 converting whereas higher concentrations resulted in secretion of f-glucuronidase and additional lysozyme without Correspondence: Dr K. F. Austen, 604 Seeley G. Mudd further release of dipeptidase. Thus, human PMNs Building, 250 Longwood Avenue, Boston, Massachusetts can convert LTD4 to LTE4, a less vasoactive and 02115, U.S.A. spasmogenic leukotriene, via the secretion of a di- Abbreviations: ATP, adenosine triphosphate; EDTA peptidase associated with the specific granules. ethylenediamine tetraacetate; Hepes, 4-(2-hydroxyethyl)-1- piperazine-ethanesulphonic acid; HBSS, Hanks's balanced salt solution; HPLC, high performance liquid chromato- graphy; LDH, lactic dehydrogenase; LTC4, leukotriene C4; INTRODUCTION LTD4, leukotriene D4; LTE4, leukotriene E4; PMA, phorbol myristate acetate; PMNs, polymorphonuclear leucocytes; The chemical constituents of slow reacting substance RP-HI'LC, reverse phase-high performance liquid chroma- tography; SRS-A, slow reacting substance of anaphylaxis; of anaphylaxis (SRS-A) are 5(S)-hydroxy-6(R)-S- y 32p;, y_32p inorganic phosphate. glutathionyl-7,9-trans, 11, 14-cis-eicosatetraenoic acid 00 1 9-2805/83/0100-0027$02.00 [leukotriene C4, (LTC4); Murphy, Hammarstrom & ©) 1983 Blackwell Scientific Publications Samuelsson, 1979; Corey, Clark, Goto, Marfat, 27 28 C. W. Lee et al. Mioskowski, Samuelsson & Hammarstr6m, 1980a] 500 ng/site (Lewis, Soter, Corey & Austen, 1981). The and its sequential cleavage products, the 6(R)-S-cys- spasmogenic and vasoactive activities that character- teinylglycyl analog [leukotriene D4 (LTD4); Bach, ize SRS-A (Brocklehurst, 1960; Drazen & Austen, Brashler, Hammarstrdm & Samuelsson, 1980; Lewis, 1974; Drazen, Lewis, Wasserman, Orange & Austen, Austen, Drazen, Clark, Marfat, & Corey, 1980a; 1979) are manifested by the entire 6-sulphido-peptide Morris, Taylor, Piper and Tippins, 1980; Orning, class of leukotrienes with some differences in potency, Hammarstrdm and Samuelsson, 1980a] and the suggesting that the conversion from LTC4 to LTD4 to 6(R)-S-cysteinyl analog (leukotriene E4 [LTE4]; Lewis, LTE4 is a cascade rather than a detoxification path- Drazen, Austen, Clark & Corey, 1980b). Based on the way. conventional definition of one unit of SRS-A as the LTC4 is sequentially converted to LTD4 and to amount that elicits a contraction of the guinea-pig LTE4 in vitro by human plasma (Parker, Koch, Huber ileum equal in amplitude to that evoked by 5 ng/ml of & Falkenhein, 1980b; Lewis, Drazen, Figueiredo, histamine, the activities of LTC4 [1 93 + 0 13 u./pmol Corey & Austen, 1982), rat basophilic leukaemia cells (mean + SD)], LTD4 (6 1 +115 u./pmol) and LTE4 (Parker, Falkenhein & Huber, 1980a; drning, Berg- (1l2+0 05 u./pmol) are 200-1000 times more potent strom & Hammarstrom, 1981), rat peritoneal eosino- than histamine on a weight basis (Lewis et al., 1980a, phil extracts (Sok, Pai, Atraches, Kang & Sih, 1981), 1980b). The potency of the leukotrienes as spas- and guinea-pig liver, lung and kidney homogenates mogens for guinea-pig parenchymal strips that con- (Sok, Pai, Atrache & Sih, 1980; Bergstrom & Ham- tain peripheral airway smooth muscles is greater than marstr6m, 1981; Sok et al., 1981), with LTE4 that of histamine by 100 times for LTC4 and LTE4 remaining as a stable end-product. Enzymatic conver- (EC5o= 3 x 10-9 M) and by 1000 times for LTD4 sion of LTC4 to LTD4 and LTC3 to LTD3 by cleavage (EC5o= 1 x 1O-10 M) (Drazen, Austen, Lewis, Clark, of glutamic acid from the S-glutathionyl domain has Goto, Marfat & Corey, 1980; Lewis et al., 1980b). been shown with y-glutamyl-transpeptidase purified LTC4 and LTD4 are 100-1000 times more potent than from kidney (Sok et al., 1980; Hammarstrom, 1981), histamine in constricting human airways in vitro and cleavage of the carboxy terminal glycine from (Dahlen, Hedqvist, Hammarstr6m & Samuelsson, LTD4 to form LTE4 has been demonstrated with 1980; Hanna, Bach, Pare & Schellenberg, 1981). commercial porcine kidney dipeptidase (Hammar- Intravenous administration of 0 5-1 0 ug/kg of LTC4, strom, 1981; Bergstrom & Hammarstr6m, 1981). The LTD4 and LTE4 to guinea-pigs leads to decreased subcellular localization of LTD4-to-LTE4 converting airway conductance and a more persistent and rela- dipeptidase activity is not defined for any tissue or cell tively greater fall in dynamic compliance, especially type. The present study shows that LTD4 dipeptidase with LTC4 and LTD4 (Drazen et al., 1980; Drazen, activity associated with the specific granules of the Venugopalan, Austen, Brion & Corey, 1982). When human polymorphonuclear leucocytes (PMNs) acts administered by aerosol, LTC4 and LTD4 at 2-20 Mg extracellularly to convert LTD4 to LTE4. doses were 3800 times more potent on a molar basis than aerosolized histamine in impairing airflow measured at 30% of vital capacity in the same normal MATERIALS AND METHODS human subjects (Holroyde, Altounyan, Cole, Dixon & Elliot, 1981; Weiss, Drazen, Coles, McFadden, Lewis, Materials Weller, Corey & Austen, 1982a; Weiss, Drazen, Hanks's balanced salt solution (HBSS, Microbiologi- McFadden, Lewis, Weller, Corey and Austen, 1982b). cal Associates, Bethesda, Md); Ficoll-Hypaque, Rats receiving intravenous LTC4, 1-10 pg/kg, mani- macromolecular dextran (Pharmacia Fine Chemicals, fest an increased total peripheral resistance and a Inc., Piscataway, N.J.); calcium ionophore A23187 decrease in cardiac output due to a direct negative (Calbiochem-Behring Corp., La Jolla, Calif.); inotropic effect (Pfeffer, Pfeffer, Lewis, Braunwald, adenosine 5'-triphosphate (ATP), atropine sul- Corey & Austen, 1982). LTC4, LTD4 and LTE4 phate, histamine diphosphate, ouabain octahydrate, increase vascular permeability in guinea-pig skin phorbol myristate acetate (PMA), phenolphthalein- (Drazen et al., 1980; Dahlen, Bjork, Hedqvist, Arfors, fl-D-glucuronide, y-glutamyl-transpeptidase, and Hammarstrom, Lindgren & Samuelsson, 1981; Peck, Micrococcus Iysodeikticus (Sigma Chemical Co., St. Piper & Williams, 1981), and elicit a wheal and flare Louis, Mo.); 4-(2-hydroxyethyl)-1-piperazine-ethane- response in human skin when injected intradermally at sulphonic acid (Hepes; Boehringer Mannheim, Conversion of LTD4 to LTE4 by human PMNs 29 Indianapolis, Ind.); cytochalasin B (Aldrich Chemical (pellet 1). The 400 g supernatant was centrifuged at Co., Milwaukee, Wisc.); adenosine 5'-triphosphate 10,000 g for 40 min at 40 to sediment the lysosomal tetra (triethyl ammonium salt), [32p], 1000-3000 granules (pellet 2). The 10,000 g supernatant was Ci/mmol (New England Nuclear Co., Boston, Mass.); centrifuged at 225,000g for 30 min at 40 to yield a final and high performance liquid chromatography supernatant (supernatant 3) and a final pellet (pellet (HPLC) grade methanol (Burdick and Jackson 3); pellet 3 was washed and centrifuged at 225,000g for Laboratories, Muskegon, Wisc.) were obtained from 30 min at 4° with 10 mm Hepes, pH 7 5, and then with I the manufacturers. LTC4, LTD4 and LTE4 were mM Hepes, pH 7 5. Pellets 1, 2 and 3 were resuspended prepared as described (Corey et al., 1980a, Lewis et al., in HBSS containing 2 5 mm MgCl2 and 2-5 mm EDTA. 1980b) and stored frozen at a concentration of A portion of the starting post-cavitation suspension, 25 ug/ml in 0-1 M phosphate buffer, pH 68:ethanol pellets 1, 2 and 3 and supernatant 3, were sonicated (4: 1, v/v) under argon until the day of use. [3H]LTC4 (power 4, 50% pulse cycle, 5 pulses, Branson Sonifier, (60 Ci/mmol), prepared by reacting [3H]leukotriene A4 Model 350, Danbury, Conn.) and assayed for lactate with glutathione (Corey, Clark, Marfat & Goto, dehydrogenase (LDH), lysozyme, fl-glucuronidase, 1980b), was provided by New England Nuclear. ouabain-inhibitable Na+K+-ATPase, protein, and [3H]LTD4 was prepared by reacting [3H]LTC4 with the capacity to convert LTD4 to LTE4. y-glutamyl-transpeptidase and purified by reverse Ten million PMNs in I ml of HBSS in 15 ml phase-HPLC (RP-HPLC) (Orning & Hammarstrom, centrifuge tubes were incubated in duplicate with or 1980). without cytochalasin B (5 pg/ml) for 5 min at 370 before the introduction ofa degranulating stimulus for Purification, subcellular fractionation and lysosomal various time intervals at 370.
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