Background: A number of different molecules are known to be involved in the signal pathway to release histamine from mast cells, among which arachidonic acid (AA) is one of the key mediators. On the other hand, we found that the application of compound 48/80, a typical histamine liberator, generated superoxide in mast cells. In the present study, we investigated the mechanism of superoxide production in mast cells with respect to AA signaling in conjunction with a fine structural analysis. Methods: Superoxide production was monitored by chemiluminescence in rat peritoneal mast cells and their subfractions after various treatments. For scanning electron micrography, the conditions for fixation and freeze-fracture were optimized to get natural fine images. Results: Compound 48/80 induced superoxide production in the isolated mast cells and some of their subfractions possibly through intracellular increase in Ca2+ concentration, activation of cytosolic phospholipase A2, and release of AA. Discussion: The present results indicate the critical role of AA in the signal pathway to generate superoxide from mast cells in response to compound 48/80.

1.
Babior BM, Kipnes RS, Curnutte JT: Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 1973;52:741–744.
2.
Curnutte JT, Babior BM: Biological defense mechanisms. The effect of bacteria and serum on superoxide production by granulocytes. J Clin Invest 1974;53:1662–1672.
3.
Johnston RB, Keele BB, Mistra HP, Lehmeyer JE, Webb LS, Baehner RL, Rajagopalan K: The role of superoxide anion generation in phagocytic bactericidal activity. Studies with normal and chronic granulomatous disease leukocytes. J Clin Invest 1975;55:1357–1372.
4.
Klebanoff SJ: Antimicrobial mechanism in neutrophilic polymorphonuclear leukocytes. Semin Hematol 1975;12:117–142.
5.
Fairshter RD, Wilson AF: Paraquat poisoning: Manifestations and therapy. Am J Med 1975;59:751–753.
6.
Schinetti ML, Mazzini A, Greco R, Bertelli A: Inhibiting effect of levamisole on superoxide production from rat mast cells. Pharmacol Res Commun 1984;16:101–107.
7.
Mannaioni PF, Masini E, Pistelli A, Salvemini D, Vane JR: Mast cells as a source of superoxide anions and nitric oxide-like factor: Relevance to histamine release. Int J Tissue React 1991;13:271–278.
8.
Fukuishi N, Sakaguchi M, Matsuura S, Nakagawa C, Akagi R, Akagi M: The mechanisms of compound 48/80-induced superoxide generation mediated by A-kinase in rat peritoneal mast cells. Biochem Mol Med 1997;61:107–113.
9.
Kennerly DA, Sullivan TJ, Sylwester P, Parker CW: Diacylglycerol metabolism in mast cells: A potential role in membrane fusion and arachidonic acid release. J Exp Med 1979;150:1039–1044.
10.
Glaser KB, Jacobs RS: Molecular pharmacology of manoalide. Inactivation of bee venom phospholipase A2. Biochem Pharmacol 1986;35:449–453.
11.
Jacobson PB, Marshall LA, Sung A, Jacobs RS: Inactivation of human synovial fluid phospholipase A2 by the marine natural product, manoalide. Biochem Pharmacol 1990;39:1557–1564.
12.
Reynolds LJ, Mihelich ED, Dennis EA: Inhibition of venom phospholipases A2 by manoalide and manoalogue. Stoichiometry of incorporation. J Biol Chem 1991;266:16512–16517.
13.
Riendeau D, Guay J, Weech PK, Laliberte F, Yergey J, Chun Li, Desmarais S, Perrier H, Liu S, Nicoll-Griffith D, Street IP: Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A2, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets. J Biol Chem 1994;269:15619–15624.
14.
Tasaka K, Mio M, Okamoto M: The role of intracellular Ca2+ in the degranulation of skinned mast cells. Agents Actions 1987;20:157–160.
15.
Cooper PH, Stanworth DR: Characterization of calcium-iron-activated adenosine triphosphatase in the plasma membrane of rat mast cells. Biochem J 1976;156:691–700.
16.
Henderson WR, Kaliner M: Immunologic and nonimmunologic generation of superoxide from mast cells and basophils. J Biol Chem 1978;61:187–196.
17.
McCord JM, Fridovich I: The utility of superoxide dismutase in studying free radical reactions. J Biol Chem 1969;244:6056–6063.
18.
Ishimoto T, Arisato K, Akiba S, Sato T: Requirement of calcium influx for hydrolytic action of membrane phospholipids by cytosolic phospholipase A2 rather than mitogen-activated protein kinase activation in Fc epsilon RI-stimulated rat peritoneal mast cells. J Biochem (Tokyo) 1996;120:1247–1252.
19.
Murakami M, Hara N, Kudo I, Inoue K: Triggering of degranulation in mast cells by exogenous type II phospholipase A2. J Immunol 1993;151:5675–5684.
20.
Nakatani Y, Hara S, Murakami M, Kudo I, Inoue K: Characterization of cytosolic phospholipase A2 in rat mastocytoma RBL-2H3. Biol Pharm Bull 1994;17:47–50.
21.
Clark JD, Schievella AR, Nalefski EA, Lin LL: Cytosolic phospholipase A2. J Lipid Mediat Cell Signal 1995;12:83–117. Review.
22.
Kramer RM, Sharp JD: Structure, function and regulation of Ca2+-sensitive cytosolic phospholipase A2 (cPLA2) (review). FEBS Lett 1997;410:49–53.
23.
Gijon MA, Leslie CC: Regulation of arachidonic acid release and cytosolic phospholipase A2 activation (review). J Leukoc Biol 1999;65:330–336.
24.
Tasaka K, Akagi M, Mio M, Miyoshi K, Nakaya N: Inhibitory effects of oxatomide on intracellular Ca mobilization, Ca uptake and histamine release, using rat peritoneal mast cells. Int Arch Allergy Appl Immunol 1987;83:348–353.
25.
Dahlgren C, Karlsson A: Respiratory burst in human neutrophils (review). J Immunol Methods 1999;232:3–14.
26.
Nauseef WM: The NADPH-dependent oxidase of phagocytes (review). Proc Assoc Am Physicians 1999;111:373–382.
27.
Kobayashi T, Seguchi H: Novel insight into current models of NADPH oxidase regulation, assembly and localization in human polymorphonuclear leukocytes (review). Histol Histopathol 1999;14:1295–1308.
28.
Jones RD, Hancock JT, Morice AH: NADPH oxidase: A universal oxygen sensor (review)? Free Radic Biol Med 2000;29:416–424.
29.
Cross AR: p40(phox) participates in the activation of NADPH oxidase by increasing the affinity of p47(phox) for flavocytochrome b(558). Biochem J 2000;349:113–117.
30.
Paclet MH, Coleman AW, Vergnaud S, Morel F: P67-phox-mediated NADPH oxidase assembly: Imaging of cytochrome b558 liposomes by atomic force microscopy. Biochemistry 2000;39:9302–9310.
31.
Badway JA, Curnutte JT, Karnovsky ML: cis-Polyunsaturated fatty acids induce high levels of superoxide production by human neutrophils. J Biol Chem 1981;256:12640–12643.
32.
Ortner MJ: The oxidation of endogenous ascorbic acid histamine secretion by rat peritoneal mast cells. Exp Cell Res 1980;129:485–487.
33.
Ballou LR, Cheung WY: Inhibition of human platelet phospholipase A2 activity by unsaturated fatty acids. Proc Natl Acad Sci USA 1985;82:371–375.
34.
Satriano JA, Shuldiner M, Hora K, Xing Y, Shan Z, Schlondorff D: Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Invest 1993;92:1564–1571.
35.
Ruiz-Gines JA, Lopez-Ongil S, Gonzalez-Rubio M, Gonzalez-Santiago L, Rodriguez-Puyol M, Rodriguez-Puyol D: Reactive oxygen species induce proliferation of bovine aortic endothelial cells. J Cardiovasc Pharmacol 2000;35:109–113.
36.
Ha HC, Thiagalingam A, Nelkin BD, Casero RA: Reactive oxygen species are critical for the growth and differentiation of medullary thyroid carcinoma cells. Clin Cancer Res 2000;6:3783–3787.
37.
Li J, Huang CY, Zheng RL, Cui KR, Li JF: Hydrogen peroxide induces apoptosis in human hepatoma cells and alters cell redox status. Cell Biol Int 2000;24:9–23.
38.
Peden DB, Dailey L, DeGraff W, Mitchell JB, Lee JG, Kaliner MA, Hohman RJ: Hydrogen peroxide effects on rat mast cell function. Am J Physiol 1994;267:L85–L93.
39.
Wolfreys K, Oliveira DB: Alterations in intracellular reactive oxygen species generation and redox potential modulate mast cell function. Eur J Immunol 1997;27:297–306.
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