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And Superoxide Anion Generation in Neutrophils of Arachidonic Acid For Distinct Phospholipases A2 Regulate the Release of Arachidonic Acid for Eicosanoid Production and Superoxide Anion Generation in Neutrophils This information is current as Patricia K. Tithof, Marc Peters-Golden and Patricia E. Ganey of October 2, 2021. J Immunol 1998; 160:953-960; ; http://www.jimmunol.org/content/160/2/953 References This article cites 50 articles, 27 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/160/2/953.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Distinct Phospholipases A2 Regulate the Release of Arachidonic Acid for Eicosanoid Production and Superoxide Anion Generation in Neutrophils1 Patricia K. Tithof,* Marc Peters-Golden,‡ and Patricia E. Ganey2*† Arachidonic acid (AA) released from membrane phospholipids by phospholipase A2 (PLA2) is important as a substrate for 2 eicosanoid formation and as a second messenger for superoxide anion (O2 ) generation in neutrophils. Different isoforms of PLA2 in neutrophils might mobilize AA for different functions. To test this possibility, we sought to characterize the PLA2s that are activated by the neutrophil stimuli, Aroclor 1242, a mixture of polychlorinated biphenyls, and A23187, a calcium ionophore. 3 2 Both Aroclor 1242 and A23187 caused release of [ H]AA; however, O2 production was seen only in response to Aroclor 1242. Eicosanoids accounted for >85% of the radioactivity recovered in the supernatant of A23187-stimulated cells but <20% of the Downloaded from radioactivity recovered from cells exposed to Aroclor 1242. Omission or chelation of calcium abolished A23187-induced AA 2 release, but did not alter AA release in Aroclor 1242-stimulated neutrophils. AA release and O2 production in response to Aroclor 1242 were inhibited by bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2. BEL, however, did not alter A23187-induced release of AA. Cell-free assays demonstrated both calcium-dependent and calcium-independent PLA2 activity. Calcium-independent activity was inhibited >80% by BEL, whereas calcium-dependent activity was inhibited <5%. Further- more, calcium-independent, but not calcium-dependent, PLA activity was significantly enhanced by Aroclor 1242. These data 2 http://www.jimmunol.org/ suggest that Aroclor 1242 and A23187 activate distinct isoforms of PLA2 that are linked to different functions: Aroclor 1242 2 activates a calcium-independent PLA2 that releases AA for the generation of O2 , and A23187 activates a calcium-dependent PLA2 that mobilizes AA for eicosanoid production. The Journal of Immunology, 1998, 160: 953–960. 3 rachidonic acid (AA) serves as a precursor for the gen- (PLA2)-dependent hydrolysis of sn-2-acyl ester bonds. Several dif- eration of a family of bioactive lipid mediators known as ferent isoforms of PLA2 have been described that represent distinct A eicosanoids that includes prostaglandins, thromboxanes, gene products. These include two well-characterized, small-m.w., and leukotrienes. The roles of these products in normal physiologic calcium-dependent enzymes that are not selective for AA, the14- function (1) as well as in pathophysiologic states (2) have been by guest on October 2, 2021 kDa secretory PLA2 and pancreatic PLA2 (13, 14); an 85-kDa well documented. More recently, AA itself, as well as other un- cytosolic PLA2 (cPLA2), which is calcium dependent and arachi- saturated fatty acids, has been shown to serve important functions donoyl selective (15–17); and two calcium-independent enzymes, as second messengers. AA regulates such processes as activation one of which is selective for AA (18–20) and one that is not of protein kinase C (3) and mitogen-activated protein kinases (4), (21–23). Many cell types including neutrophils contain multiple synthesis of heat shock proteins (5), mobilization of intracellular isoforms of PLA2 (24–26); however, the functional significance of calcium and activation of calcium channels (6, 7), and modulation the presence of different isoforms within the cell is not well un- of the activity of potassium channels (8, 9). In addition, AA and derstood. It has been suggested that different PLA s within the cell other unsaturated fatty acids may play an essential role in activa- 2 carry out distinct biologic functions (26). tion of the enzyme NADPH oxidase, which is responsible for the 2 In neutrophils, PLA -derived AA is important as a substrate for generation of superoxide anion (O ) by neutrophils (10–12). 2 2 eicosanoid production. AA has also been implicated as a second An important pathway for the release of AA or other unsaturated messenger for generation of O2, which is essential for neutrophil- fatty acids from phospholipid pools involves phospholipase A 2 2 mediated killing of microbial pathogens (10–12); however, this function remains controversial (27). In support of a role for AA in 2 2 † Departments of *Pharmacology and Toxicology, and Medicine and Institute for generation of O2 , virtually all agents that stimulate O2 production Environmental Toxicology, Michigan State University, East Lansing, MI 48824; in neutrophils also cause the release of AA (11, 12, 28). In addi- and ‡Division of Pulmonary and Critical Care Medicine, Department of Medi- cine, University of Michigan, Ann Arbor, MI 48109 tion, experiments with intact cells, as well as with reconstituted Received for publication November 26, 1997. Accepted for publication October NADPH oxidase systems, suggest that AA, rather than its metab- 1, 1997. olites, regulates a hydrogen ion channel that is linked to NADPH The costs of publication of this article were defrayed in part by the payment of oxidase activity (29, 30). It has been suggested that arachidonate page charges. This article must therefore be hereby marked advertisement in plays an important role in assembly of oxidase components by accordance with 18 U.S.C. Section 1734 solely to indicate this fact. exposing SH3 domains of p47phox, thus allowing interaction with 1 This work was supported by National Institutes of Health Grant ESO4911. cytochrome b558 and p67phox (31). 2 Address correspondence and reprint requests to Dr. Patricia E. Ganey, Depart- ment of Pharmacology and Toxicology, B440 Life Sciences, Michigan State Uni- PLA2-mediated AA release appears to play an essential role in versity, East Lansing, MI 48824. 2 production of O2 by neutrophils upon exposure to the commercial 3 2 Abbreviations used in this paper: AA, arachidonic acid; O2 , superoxide anion; mixture of polychlorinated biphenyls (PCBs), Aroclor 1242 (28). PLA2, phospholipase A2; cPLA2, cytosolic PLA2; BEL, bromoenol lactone; LDH, lactate dehydrogenase; HETE, hydroxyeicosatetraenoic acid; PCB, polychlori- PCBs are environmental toxicants that cause diverse biologic ef- nated biphenyl; TCB, tetrachlorobiphenyl; SOD, superoxide dismutase. fects, including modulation of inflammatory-mediated responses Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 954 PHOSPHOLIPASE A2 AND NEUTROPHIL FUNCTION such as neutrophil-mediated liver injury (32). Aroclor 1242 con- incubation period, neutrophils were washed two times with Mg21- and 1 sists of a complex mixture of coplanar and ortho-substituted, non- Ca2 -free HBSS. The cell count was adjusted so that the final concentra- 3 6 3 coplanar PCB congeners. Release of AA and production of O2 can tion of neutrophils was 2 10 /ml. The incorporation of H-AA was 2 approximately 60% and that of [3H]linoleic acid was approximately 70% be attributed to the ortho-substituted congeners within the mixture, of the total radioactivity added to the cells. since congeners such as 2,29,4,49-tetrachlorobiphenyl (TCB) stim- 2 ulate both the release of AA and the generation of O2 , whereas coplanar congeners such as 3,39,4,49-TCB cause neither Determination of fatty acid release from prelabeled effect (28). neutrophils The magnitude of release of AA in response to Aroclor 1242 is Prelabeled neutrophils were suspended in HBSS containing 0.1% BSA. In similar to that observed from neutrophils stimulated with the cal- these experiments BSA was used to trap released fatty acids, thus inhibiting cium ionophore, A23187. However, the fate of released AA in subsequent metabolism and reacylation: as a result, the radioactivity in the supernatant reflects cumulative deacylation of [3H]fatty acid from phos- response to these two stimuli may be different. AA released from pholipid pools. Release of [3H]fatty acid was determined in the presence A23187-stimulated neutrophils is metabolized extensively to eico- and absence of the inhibitor of the calcium-independent PLA2, BEL. Neu- sanoids (33); however, A23187 does not stimulate the production trophils were
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