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C5a Is Independent of Phospholipase Activation (Chemotactic Factors/Arachidonic Acid/Lipoxygenase/Chemotaxis/Human Neutrophils) ROBERT M

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C5a Is Independent of Phospholipase Activation (Chemotactic Factors/Arachidonic Acid/Lipoxygenase/Chemotaxis/Human Neutrophils) ROBERT M Proc. Natl. Acad. Sci. USA Vol. 80, pp. 7200-7204, December 1983 Cell Biology Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl-Met-Leu-Phe or complement component C5a is independent of phospholipase activation (chemotactic factors/arachidonic acid/lipoxygenase/chemotaxis/human neutrophils) ROBERT M. CLANCY, CLEMENS A. DAHINDEN, AND TONY E. HUGLI Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037 Communicated by HansJ. Muller-Eberhard, July 18, 1983 ABSTRACT Release of arachidonic acid by the membrane tactic factors appear capable of modulating a number of other phospholipase and metabolism by the 5-lipoxygenase pathway was aspects of the inflammatory reaction. examined in human polymorphonuclear leukocytes (PMNs). The Recently, another class of chemotactic factor was described. 5-lipoxygenase pathway is activated when PMNs are given arach- The biologically active principle, leukotriene B4 (LTB4), is a idonic acid in ethanol and there is extensive metabolism to 5-hy- complex lipid found to be as potent on a molar basis as the for- droxyicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). myl peptides or C5a (7-9). LTB4 is a metabolite of arachidonic This activation event was shown to be altered by the ethanol be- acid formed by the 5-lipoxygenase pathway. Arachidonic acid cause resting PMNs given arachidonic acid with bovine serum al- does not exist in free form but is normally esterified in tri- bumin fail to metabolize arachidonic acid. However, cells acti- vated by the inflammatory agents N-formyl-Met-Leu-Phe (fMLF) glycerides and phospholipids in the cell membrane. It has been or complement component C5a recruit the 5-lipoxygenase to me- postulated that granulocyte stimulation activates membrane tabolize exogenous arachidonic acid to 5-HETE and LTB4. When phospholipase(s) to release arachidonic acid, which is then en- PMNs were incubated with arachidonic acid-bovine serum al- zymatically metabolized by the 5-lipoxygenase pathway to form bumin and challenged with fMLF or C5a (des-Arg-C5a) they pro- LTB4 as well as a host of other bioactive lipid metabolites (10, duced 49-75 pmol of LTB4 and 310-440 pmol of 5-HETE per 107 11). cells. PMNs stimulated by fMLF or C5a (des-Arg-C5a) do not in- PMNs not only respond when exposed to LTB4 but also are duce membrane phospholipases to mobilize endogenous arachi- a major source of this factor when stimulated by the calcium donic acid and neither 5-HETE nor LTB4 is formed. In contrast, ionophore A23187 (12). Thus LTB4 may serve as an intracel- PMN stimulation by the ionophore A23187 activates both the lular second messenger in the receptor-response coupling of membrane phospholipase and the 5-lipoxygenase to produce 5- PMN stimulated by other chemotactic factors (13). Indeed, sev- HETE and LTB4 from endogenous arachidonic acid. Our results eral reports support a direct role for the lipoxygenase pathway indicate that the lipoxygenase pathway is inoperative in resting of arachidonic acid metabolism in PMN activation (9, 14, 15). PMNs but can be recruited by chemotactic factors to act on arach- In order to establish the role of LTB4 in inflammatory reac- idonate from extracellular sources. It was previously believed that tions, the physiological conditions leading to release of this lipid formation of 5-HETE and LTB4 by the PMN depends solely on mediator must first be examined. phospholipase to mobilize endogenous arachidonic acid. The In this study, we examined 5-lipoxygenase metabolites of results reported here refute this concept and indicate that the arachidonate that are formed by PMNs exposed to the chemo- role of phospholipase activation in PMN may be overestimated. tactic factors N-formyl-Met-Leu-Phe (fMLF) and C5a/des-Arg- Therefore, subsequent involvement of lipoxygenase products in C5a. Our results showthat, unlike the calcium ionophore A23187, mediating stimulation of PMN by inflammatory factors (e.g., as neither C5a/des-Arg-C5a nor fMLF stimulates PMNs to me- in aggregation and chemotaxis) remains in question unless an ex- tabolize endogenous arachidonic acid into 5-hydroxyicosatetra- ogenous source of arachidonate can be identified. enoic acid (5-HETE) or LTB4. However, 5-HETE, LTB4, and Polymorphonuclear cells (PMNs) are a central component of other metabolites of the lipoxygenase pathway are formed from the cellular response in inflammatory reactions and of para- exogenous arachidonic acid by PMNs stimulated with chemo- mount importance to the immune surveillance system. PMNs tactic factors. Conversely, exogenous arachidonic acid is not are attracted to inflammatory sites in a highly specific manner metabolized by PMNs in the resting state. These results in- by stimulation from chemotactic factors. Many chemotactic fac- dicate the phospholipase(s) that releases intracellular arachi- tors have been described, but only those derived from the fifth donic acid is either poorly activated or unactivated when PMNs component of complement (e.g., C5a and des-Arg-C5a) and are stimulated by fMLF or C5a. Conversely, the 5-lipoxygen- synthetic analogues of the putative bacterial chemotactic factor ase that does not metabolize arachidonic acid in resting PMNs (e.g., N-formyl peptides) have been thoroughly characterized is activated by fMLF and C5a. (1, 2). These agents, in the nanomolar concentration range, bind and activate the PMNs by interacting with distinct receptor sites METHODS to induce directional migration of the PMN (3, 4). They also Cell Preparation and Reaction Conditions. Venous blood stimulate other cellular functions such as aggregation, adher- from human adult donors was collected into sodium heparin (20 ence, enzyme release, and the production of toxic oxygen me- tabolites (3, 5, 6). Thus, in addition to attracting PMNs, chemo- Abbreviations: monoHETE, monohydroxyicosatetraenoic acid; di- HETE, dihydroxyicosatetraenoic acid; 5-HETE, 5-hydroxyicosatetrae- The publication costs of this article were defrayed in part by page charge noic acid; LTB4, (5S,12R)-cis-trans-trans-dihydroxyicosatetraenoic acid payment. This article must therefore be hereby marked "advertise- (leukotriene B4); PMN, polymorphonuclear cell; fMLF, N-formyl-Met- ment" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Leu-Phe; C5a, a fragment of the fifth component of complement. 7200 Downloaded by guest on September 30, 2021 Cell Biology: Clancy et A Proc. Natl. Acad. Sci. USA 80 (1983) 7201 units/ml of blood). PMNs were purified according to the method we challenged 108 PMNs with 250 nmol of arachidonic acid and of Dahinden and co-workers (16), which involved separating measured oxygen consumption with an oxygen electrode, we erythrocytes by layering the blood on methylcellulose/metri- observed no burst in oxygen consumption (Fig. 1). However, zoate followed by purifying the leukocyte-rich supernatant on cells subsequently challenged with 1 AuM fMLF underwent a Ficoll/Hypaque. The residual erythrocytes were removed by burst of oxygen consumption reflecting stimulation of the hex- hypotonic lysis and the PMNs were washed twice in Gey's so- ose monophosphate shunt and production of O2 (6, 19). The lution. The PMN preparation contained less than 0.5% mono- respiratory burst initiated by fMLF was identical with or with- nuclear cells and less than 0.01% platelets. This purification out arachidonic acid pretreatment of the PMNs (data not shown). method has a low platelet contamination compared to cell prep- Supernatants from suspensions of stimulated cells were arations that use dextran in the first purification step. The PMNs screened for production of monoHETE or diHETE metabo- were resuspended at 2.5 x 107 cells per ml in a modified Ty- lites of arachidonic acid. The lipid components in these su- rode buffer. The bicarbonate concentration of the Tyrode buff- pernatants were isolated and analyzed on HPLC. PMNs pro- er was reduced to 1.6 mM, and 10 mM Hepes, 2 mM glucose, duce numerous lipoxygenase metabolites when challenged with and 1% fatty acid-free bovine serum albumin (Miles; hereafter the calcium ionophore A23187, as is shown in Fig. 2A. A major referred to as albumin) were added. metabolite is (5S,12R)-cis-trans-trans-diHETE (LTB4), which Arachidonic acid (99% pure, Calbiochem or Nu Chek Prep) is designated here as compound ml and has a retention time of was stored under N2 gas in methanol at -20°C. When cells were 14.0 min. Another major metabolite is 5-HETE, which has a challenged with arachidonic acid in the presence of albumin, retention time of 45.0 min. Note that even with ionophore- an aliquot of arachidonic acid was dried under N2 gas and the stimulated cells no platelet-derived lipoxygenase products such arachidonic acid was suspended in the modified Tyrode buffer as 12-hydroxyicosatetraenoic acid or 12-hydroxyheptadecatri- by vigorously swirling on a Vortex mixer. For the activation of enoic acid were detected, further indicating the low platelet cells by chemotactic factors, 1 ml of the cell suspension was content of our cell preparation. The supernatant from cells that incubated for 5 min at 37°C and then another 5 min after ad- were exposed only to arachidonic acid bound to albumin con- dition of arachidonic acid. After a total of 10 min at 37°C, the tain no detectable monoHETE or diHETE metabolites (Fig. cells were challenged with fMLF, C5a, or des-Arg-C5a. 2B). An identical chromatographic pattern was observed when Analysis of Arachidonate Products. For the analysis of leu- the PMNs were stimulated with fMLF in the absence of arach- kotrienes, the cells were lysed by addition of 1 vol of methanol idonic acid. However, supernatants from cells first given arach- per sample volume. The cell debris was spun down and the su- idonic acid and then challenged by fMLF contain large quan- pernatant was recovered. The pellet was washed with 1 vol of tities of 5-HETE and the isomers of LTB4 (Fig. 2C). methanol, and after centrifugation, the wash was combined with Conversion of extracellular arachidonic acid to lipoxygenase the reaction supernatant.
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