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W2058902360 abstract "We investigated the possible involvement of group VI Ca2+-independent phospholipase A2(iPLA2) in arachidonic acid (AA) liberation in zymosan-stimulated macrophage-like P388D1 cells. Zymosan-induced AA liberation was markedly inhibited by methyl arachidonoyl fluorophosphonate, a dual inhibitor of group IV cytosolic phospholipase A2 (cPLA2) and iPLA2. We found that a relatively specific iPLA2 inhibitor, bromoenol lactone, significantly decreased the zymosan-induced AA liberation in parallel with the decrease in iPLA2 activity, without an effect on diacylglycerol formation. Consistent with this, attenuation of iPLA2 activity by a group VI iPLA2 antisense oligonucleotide resulted in a decrease in zymosan-induced prostaglandin D2 generation. These findings suggest that zymosan-induced AA liberation may be, at least in part, mediated by iPLA2. A protein kinase C (PKC) inhibitor diminished zymosan-induced AA liberation, while a PKC activator, phorbol 12-myristate 13-acetate (PMA), enhanced the liberation. Bromoenol lactone suppressed the PMA-enhanced AA liberation without any effect on PMA-induced PKC activation. Down-regulation of PKCα on prolonged exposure to PMA also decreased zymosan-induced AA liberation. Under these conditions, the remaining AA liberation was insensitive to bromoenol lactone. Furthermore, the PKC depletion suppressed increases in iPLA2 proteins and the activity in the membrane fraction of zymosan-stimulated cells. In contrast, the zymosan-induced increases in iPLA2 proteins and the activity in the fraction were facilitated by simultaneous addition of PMA. Although intracellular Ca2+ depletion prevented zymosan-induced AA liberation, the translocation of PKCα to membranes was also inhibited. Taken together, we propose that zymosan may stimulate iPLA2-mediated AA liberation, probably through a PKC-dependent mechanism. We investigated the possible involvement of group VI Ca2+-independent phospholipase A2(iPLA2) in arachidonic acid (AA) liberation in zymosan-stimulated macrophage-like P388D1 cells. Zymosan-induced AA liberation was markedly inhibited by methyl arachidonoyl fluorophosphonate, a dual inhibitor of group IV cytosolic phospholipase A2 (cPLA2) and iPLA2. We found that a relatively specific iPLA2 inhibitor, bromoenol lactone, significantly decreased the zymosan-induced AA liberation in parallel with the decrease in iPLA2 activity, without an effect on diacylglycerol formation. Consistent with this, attenuation of iPLA2 activity by a group VI iPLA2 antisense oligonucleotide resulted in a decrease in zymosan-induced prostaglandin D2 generation. These findings suggest that zymosan-induced AA liberation may be, at least in part, mediated by iPLA2. A protein kinase C (PKC) inhibitor diminished zymosan-induced AA liberation, while a PKC activator, phorbol 12-myristate 13-acetate (PMA), enhanced the liberation. Bromoenol lactone suppressed the PMA-enhanced AA liberation without any effect on PMA-induced PKC activation. Down-regulation of PKCα on prolonged exposure to PMA also decreased zymosan-induced AA liberation. Under these conditions, the remaining AA liberation was insensitive to bromoenol lactone. Furthermore, the PKC depletion suppressed increases in iPLA2 proteins and the activity in the membrane fraction of zymosan-stimulated cells. In contrast, the zymosan-induced increases in iPLA2 proteins and the activity in the fraction were facilitated by simultaneous addition of PMA. Although intracellular Ca2+ depletion prevented zymosan-induced AA liberation, the translocation of PKCα to membranes was also inhibited. Taken together, we propose that zymosan may stimulate iPLA2-mediated AA liberation, probably through a PKC-dependent mechanism. arachidonic acid bromoenol lactone platelet-activating factor protein kinase C phospholipase A2 cytosolic PLA2 Ca2+-independent PLA2 phorbol 12-myristate 13-acetate The liberation of arachidonic acid (AA)1 upon stimulation is an important event leading to the generation of biologically active lipid mediators, such as prostaglandins and leukotrienes, and is mainly dependent on the hydrolysis of membrane glycerophospholipids catalyzed by phospholipase A2 (PLA2) (1van den Bosch H. Biochim. Biophys. Acta. 1980; 604: 191-246Crossref PubMed Scopus (826) Google Scholar, 2Waite M. J. Lipid Res. 1985; 26: 1379-1388Abstract Full Text PDF PubMed Google Scholar). Numerous types of mammalian PLA2s have been identified and classified into several groups (3Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). The mammalian PLA2s include at least two types of intracellular PLA2s,i.e. Ca2+-dependent and -independent enzymes. It is widely accepted that the intracellular PLA2 responsible for stimulus-induced AA liberation is group IV Ca2+-dependent cytosolic PLA2 (cPLA2), which preferentially hydrolyzes glycerophospholipids with an arachidonoyl residue at thesn-2 position (4Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 1170: 217-231Crossref PubMed Scopus (371) Google Scholar, 5Leslie C.C. J. Biol. Chem. 1997; 272: 16709-16712Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar). The activation of cPLA2upon stimulation is mediated by Ca2+-dependent translocation to membranes (6Channon J.Y. Leslie C.C. J. Biol. Chem. 1990; 265: 5409-5413Abstract Full Text PDF PubMed Google Scholar, 7Glover S. Bayburt T. Jonas M. Chi E. Gelb M.H. J. Biol. Chem. 1995; 270: 15359-15367Crossref PubMed Scopus (314) Google Scholar), and by mitogen-activated protein kinase-catalyzed phosphorylation (8Lin L.-L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. Davis R.J. Cell. 1993; 72: 269-278Abstract Full Text PDF PubMed Scopus (1643) Google Scholar, 9Nemenoff R.A. Winitz S. Qian N.-X. Putten V.V. Johnson G.L. Heasley L.E. J. Biol. Chem. 1993; 268: 1960-1964Abstract Full Text PDF PubMed Google Scholar). On the other hand, Ca2+-independent PLA2 (iPLA2) has been detected in a variety of cells and tissues (reviewed in Ref. 10Ackermann E.J. Dennis E.A. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar). Among several types of iPLA2s, which have been purified, sequenced, and well characterized (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar, 12Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 13Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 14Ma Z. Ramanadham S. Kempe K. Chi X.S. Ladenson J. Turk J. J. Biol. Chem. 1997; 272: 11118-11127Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 15Larsson P.K.A. Claesson H.E. Kennedy B.P. J. Biol. Chem. 1998; 273: 207-214Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), group VI iPLA2in mouse macrophage-like P388D1 cells has been proposed to participate in phospholipid remodeling rather than stimulus-induced AA liberation (16Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (255) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar).A recent study involving P388D1 cells has demonstrated that platelet-activating factor (PAF)-induced AA liberation is suppressed by an inhibitor of group IIA secretory PLA2 or cPLA2, but not by a relatively specific iPLA2inhibitor, bromoenol lactone (BEL) (18Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar). Furthermore, blockage of group V secretory PLA2 by antisense oligonucleotides partially inhibits PAF-induced prostaglandin E2 generation (19Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar), while a group VI iPLA2 antisense oligonucleotide has no effect (20Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). These findings clearly indicate that PAF-induced AA liberation may be mediated by group V secretory PLA2 and cPLA2, but not by iPLA2. Moreover, a recent report suggested that activation of cPLA2 is required for the onset of secretory PLA2-catalyzed hydrolysis of membrane phospholipids (21Balsinde J. Balboa M.A. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7951-7956Crossref PubMed Scopus (171) Google Scholar). Therefore, in PAF-stimulated P388D1 cells, cPLA2 activation may be a predominant step in the induction of AA liberation. However, while in mouse peritoneal macrophages, zymosan stimulates cPLA2activation in parallel with AA liberation (22Qui Z.-H. Leslie C.C. J. Biol. Chem. 1994; 269: 19480-19487Abstract Full Text PDF PubMed Google Scholar, 23Qui Z.-H. Gijón M.A. de Carvalho M.S. Spencer D.M. Leslie C.C. J. Biol. Chem. 1998; 273: 8203-8211Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar), zymosan-induced AA liberation in mouse macrophage-like RAW 264.7 cells has been shown to be sensitive to BEL (24Gross R.W. Rudolph A.E. Wang J. Sommers C.D. Wolf M.J. J. Biol. Chem. 1995; 270: 14855-14858Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Therefore, it is possible that iPLA2, in addition to cPLA2, might be involved in AA liberation induced by zymosan but not by PAF. Similar inhibitory effects of BEL on AA liberation have been reported in several types of cells (25Lannartz M.R. Lefkowith J.B. Bromley F.A. Brown E.J. J. Leukocyte Biol. 1993; 54: 389-398Crossref PubMed Scopus (40) Google Scholar, 26Derrickson B.H. Mandel L.J. Am. J. Physiol. 1997; 272: F781-F788PubMed Google Scholar, 27Becker B.B. Cheng H.-F. Harris R.C. Am. J. Physiol. 1997; 273: F554-F562PubMed Google Scholar, 28Wolf M.J. Wang J. Turk J. Gross R.W. J. Biol. Chem. 1997; 272: 1522-1526Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 29Atsumi G. Tajima M. Hadano A. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 13870-13877Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). However, BEL is reported to inhibit phosphatidic acid phosphatase, leading to the suppression of stimulus-induced diacylglycerol formation (30Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 31Balboa M.A. Balsinde J. Dennis E.A. J. Biol. Chem. 1998; 273: 7684-7690Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). This inhibitory effect may explain the inhibition of AA liberation by BEL, because diacylglycerol may contribute to AA liberation through direct and/or indirect modulation of cPLA2 activity (31Balboa M.A. Balsinde J. Dennis E.A. J. Biol. Chem. 1998; 273: 7684-7690Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar) or through the hydrolytic action of lipases toward diacylglycerol (32Ishimoto T. Akiba S. Sato T. J. Biochem. 1996; 120: 616-623Crossref PubMed Scopus (10) Google Scholar). It has been shown that zymosan-induced AA liberation is decreased by a protein kinase C (PKC) inhibitor (22Qui Z.-H. Leslie C.C. J. Biol. Chem. 1994; 269: 19480-19487Abstract Full Text PDF PubMed Google Scholar, 33Huwiler A. Pfeilschifter J. Eur. J. Biochem. 1993; 217: 69-75Crossref PubMed Scopus (29) Google Scholar, 34Fernández B. Balboa M.A. Solı́s-Herruzo J.A. Balsinde J. J. Biol. Chem. 1994; 269: 26711-26716Abstract Full Text PDF PubMed Google Scholar) or intracellular Ca2+ depletion (23Qui Z.-H. Gijón M.A. de Carvalho M.S. Spencer D.M. Leslie C.C. J. Biol. Chem. 1998; 273: 8203-8211Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar,34Fernández B. Balboa M.A. Solı́s-Herruzo J.A. Balsinde J. J. Biol. Chem. 1994; 269: 26711-26716Abstract Full Text PDF PubMed Google Scholar, 35Fernández B. Balsinde J. Biochem. Biophys. Res. Commun. 1991; 180: 1036-1040Crossref PubMed Scopus (17) Google Scholar) in mouse peritoneal macrophages. These findings may support the concept that cPLA2 contributes to the AA liberation, although it has been suggested that cPLA2 activation in P388D1 cells is not mediated by PKC (36Balsinde J. Balboa M.A. Insel P.A. Dennis E.A. Biochem. J. 1997; 321: 805-809Crossref PubMed Scopus (57) Google Scholar). Thus, the participation of iPLA2 in stimulus-induced AA liberation remains to be elucidated.In the present study, to clarify the role of iPLA2 upon stimulation, we explored the possible involvement of group VI iPLA2 in AA liberation in zymosan-stimulated P388D1 cells by evaluating the effects of BEL and a group VI iPLA2 antisense oligonucleotide, which have been shown to attenuate iPLA2 activity in P388D1 cells (16Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (255) Google Scholar, 20Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). We further examined the role of PKC in iPLA2-mediated AA liberation.DISCUSSIONIn the present study, we explored the possible involvement of iPLA2 in stimulus-induced AA liberation using zymosan-stimulated mouse macrophage-like P388D1 cells, which possess group VI iPLA2, one of the purified and sequenced iPLA2s (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar, 13Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). The group VI iPLA2in P388D1 cells has been shown to be inhibited by BEL, a relatively selective iPLA2 inhibitor (42Ackermann E.J. Conde-Frieboes K. Dennis E.A. J. Biol. Chem. 1995; 270: 445-450Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar). Based on the inhibitory effect of BEL on the incorporation of arachidonic acid into phospholipids (16Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (255) Google Scholar), it has been recognized that group VI iPLA2 participates in phospholipid remodeling. Furthermore, in PAF-stimulated P388D1 cells, AA liberation is partially suppressed by a secretory PLA2 inhibitor or methyl arachidonyl fluorophosphonate, a dual inhibitor of cPLA2 and iPLA2, but not by BEL (18Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 6758-6765Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar), suggesting that PAF-induced AA liberation is mediated by cPLA2 and secretory PLA2, but not by group VI iPLA2. However, as shown in this study, we found that BEL significantly decreased the zymosan-induced AA liberation under the conditions where BEL actually suppressed iPLA2 activity but not cPLA2 activity in P388D1 cells (Fig. 2), suggesting the involvement of group VI iPLA2 in the response to zymosan.A recent report demonstrated that BEL inhibits phosphatidic acid phosphatase activity, resulting in suppression of the conversion of phosphatidic acid to diacylglycerol in P388D1 cells (30Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). Furthermore, in human amnionic WISH cells, the inhibition by BEL of stimulus-induced AA liberation has been suggested to be due to the impairment of diacylglycerol-mediated cPLA2 regulation through the suppression of diacylglycerol formation (31Balboa M.A. Balsinde J. Dennis E.A. J. Biol. Chem. 1998; 273: 7684-7690Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Although a number of studies have also demonstrated that stimulus-induced AA liberation is inhibited by BEL in a variety of cells including zymosan-stimulated macrophage-like RAW 264.7 cells (24Gross R.W. Rudolph A.E. Wang J. Sommers C.D. Wolf M.J. J. Biol. Chem. 1995; 270: 14855-14858Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Lannartz M.R. Lefkowith J.B. Bromley F.A. Brown E.J. J. Leukocyte Biol. 1993; 54: 389-398Crossref PubMed Scopus (40) Google Scholar, 26Derrickson B.H. Mandel L.J. Am. J. Physiol. 1997; 272: F781-F788PubMed Google Scholar, 27Becker B.B. Cheng H.-F. Harris R.C. Am. J. Physiol. 1997; 273: F554-F562PubMed Google Scholar, 28Wolf M.J. Wang J. Turk J. Gross R.W. J. Biol. Chem. 1997; 272: 1522-1526Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 29Atsumi G. Tajima M. Hadano A. Nakatani Y. Murakami M. Kudo I. J. Biol. Chem. 1998; 273: 13870-13877Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar), it is unclear whether or not BEL affects diacylglycerol formation in these cells. However, the present study showed that 2–5 μm BEL suppressed zymosan-induced AA liberation by about 45%, without a significant change in diacylglycerol formation (Fig. 2) or phosphatidic acid formation (data not shown). Therefore, we suggest that the attenuation by BEL of zymosan-induced AA liberation may be due to inhibition of group VI iPLA2 rather than phosphatidic acid phosphatase.We further found that a group VI iPLA2 antisense oligonucleotide decreased iPLA2 activity and zymosan-induced prostaglandin D2 generation, while a sense oligonucleotide had no effect (Fig. 3). Furthermore, the antisense oligonucleotide did not affect Ca2+ionophore-induced prostaglandin D2 generation (data not shown) or the conversion of exogenous AA to prostaglandin D2. These results appear to indicate that attenuation by the antisense oligonucleotide of zymosan-induced prostaglandin D2 generation is due to the inhibition of iPLA2activity but not cPLA2 or cyclooxygenase activity. In contrast to zymosan, a recent report has shown that the group VI iPLA2 antisense oligonucleotide does not affect PAF-induced AA liberation despite the attenuation of iPLA2 activity in P388D1 cells (20Balsinde J. Balboa M.A. Dennis E.A. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). Although it is unclear whether or not the different effects of the antisense oligonucleotide on zymosan- and PAF-induced AA liberation are due to differences in the signaling pathways responsible for zymosan and PAF, we propose that group VI iPLA2 may be, at least in part, involved in zymosan-induced AA liberation in P388D1 cells.In mouse peritoneal macrophages, zymosan-induced AA liberation has been shown to occur in parallel with cPLA2 activation (22Qui Z.-H. Leslie C.C. J. Biol. Chem. 1994; 269: 19480-19487Abstract Full Text PDF PubMed Google Scholar, 23Qui Z.-H. Gijón M.A. de Carvalho M.S. Spencer D.M. Leslie C.C. J. Biol. Chem. 1998; 273: 8203-8211Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). Furthermore, a PKC inhibitor has been shown to suppress the AA liberation with concomitant decreases in mitogen-activated protein kinase and cPLA2 activities (22Qui Z.-H. Leslie C.C. J. Biol. Chem. 1994; 269: 19480-19487Abstract Full Text PDF PubMed Google Scholar). These findings suggest that cPLA2-mediated AA liberation may be regulated by PKC-dependent activation of mitogen-activated protein kinase in mouse peritoneal macrophages. We showed here that GF109203X, a PKC inhibitor, decreased zymosan-induced AA liberation, while PMA, a PKC activator, potentiated the AA liberation in P388D1 cells (Fig. 4), suggesting that PKC may be involved in zymosan-induced AA liberation. However, it is possible that the PKC-dependent AA liberation is not mediated by cPLA2, since it has been demonstrated that PKC does not participate in cPLA2 regulation in P388D1 cells (36Balsinde J. Balboa M.A. Insel P.A. Dennis E.A. Biochem. J. 1997; 321: 805-809Crossref PubMed Scopus (57) Google Scholar). In this study, BEL partially inhibited zymosan-induced AA liberation (Fig. 2), while methyl arachidonyl fluorophosphonate did so almost completely in P388D1 cells (Fig. 1), thus indicating that cPLA2 may be involved in the BEL-insensitive AA liberation.The present study demonstrated that BEL suppressed PMA-enhanced AA liberation in response to zymosan without any effect on PMA-induced PKC activation (Figs. 5 and 6), suggesting the possible involvement of iPLA2 in PKC-dependent AA liberation. We also showed that the depletion of PKCα on prolonged exposure to PMA reduced zymosan-induced AA liberation, and further that the treatment of PKC-depleted cells with BEL did not inhibit the remaining, PKC-independent AA liberation (Fig. 7). Thus, BEL seems to affect only PKC-dependent AA liberation in response to zymosan. In addition, we confirmed that BEL had no effect on zymosan-induced PKCα translocation (Fig. 7). Therefore, it is conceivable that iPLA2-mediated AA liberation may occur downstream of PKC activation in P388D1 cells. We further demonstrated that zymosan increased iPLA2 activity in the membrane fraction with a decrease in the activity in the cytosol fraction (Fig. 8). Of interest was the finding that the depletion of PKCα inhibited zymosan-induced increases in iPLA2 activity and the enzyme proteins in the membrane fraction (Fig. 8). Moreover, the increases in iPLA2 proteins and the activity in response to zymosan were potentiated by simultaneous stimulation with PMA (Fig. 9), this being consistent with the result that PMA enhanced BEL-sensitive AA liberation in zymosan-stimulated cells (Fig. 5). These findings suggest that PKC may be involved in the zymosan-induced increase in iPLA2 in the membrane fraction, due to translocation of the enzyme to the membranes. We propose this idea as one of mechanisms underlying PKC-dependent iPLA2 regulation. It has been reported that iPLA2 activity in membranes increases upon stimulation in human monocytes (43Karimi K. Lennartz M.R. J. Immunol. 1995; 155: 5786-5794PubMed Google Scholar) and rat ventricular myocytes (44Liu S.J. McHowat J. Am. J. Physiol. 1998; 275: H1462-H1472PubMed Google Scholar). In the monocytes, the membrane-associated iPLA2 activity has been suggested to be modulated by phosphorylation of the enzyme. However, although at present we have no evidence suggesting that iPLA2 may undergo phosphorylation upon stimulation with zymosan or PMA, group VI iPLA2 of P388D1 cells were suggested to have no known consensus sequence for phosphorylation sites (13Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). Based on these findings, it is possible that occurrence of iPLA2-mediated AA liberation in response to zymosan may be, at least in part, regulated by PKC-dependent iPLA2 translocation to the membranes.Stimulus-induced AA liberation in most cases occurs in a Ca2+-dependent manner, and therefore it is reasonable to consider that the liberation is catalyzed by Ca2+-dependent PLA2. In mouse peritoneal macrophages, zymosan-induced AA liberation has been shown to be suppressed by intracellular Ca2+ depletion (23Qui Z.-H. Gijón M.A. de Carvalho M.S. Spencer D.M. Leslie C.C. J. Biol. Chem. 1998; 273: 8203-8211Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 34Fernández B. Balboa M.A. Solı́s-Herruzo J.A. Balsinde J. J. Biol. Chem. 1994; 269: 26711-26716Abstract Full Text PDF PubMed Google Scholar, 35Fernández B. Balsinde J. Biochem. Biophys. Res. Commun. 1991; 180: 1036-1040Crossref PubMed Scopus (17) Google Scholar). We also showed that zymosan-induced AA liberation was not observed in the presence of intracellular and extracellular Ca2+chelators in P388D1 cells (Fig. 10). These findings may indicate that iPLA2 is not involved in the mechanism underlying the zymosan-induced AA liberation, because iPLA2does not require Ca2+ for its catalytic action. However, we demonstrated that intracellular Ca2+ depletion prevented zymosan-induced PKCα translocation (Fig. 10). Since the activation of PKCα is supposed to be upstream of iPLA2-mediated AA liberation (Fig. 7), it seems likely that the inhibition of zymosan-induced AA liberation by intracellular Ca2+depletion is probably due to, at least in part, the suppression of PKC activation.In this study, although PMA enhanced zymosan-induced AA liberation and iPLA2 translocation to the membranes, PMA by itself did not cause these responses (Figs. 4 and 9). This may suggest that PKC activation is essential for zymosan-induced AA liberation but insufficient for iPLA2 regulation. It has been demonstrated that a recombinant 80-kDa iPLA2 associates with calmodulin in a Ca2+-dependent manner (45Wolf M.J. Gross R.W. J. Biol. Chem. 1996; 271: 30879-30885Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). In P388D1 cells, zymosan-induced AA liberation was sensitive to W-7, a calmodulin antagonist. 2S. Akiba, K. Kume, S. Mizunaga, and T. Sato, unpublished observation. Therefore, we speculate that PKC might regulate iPLA2-mediated AA liberation in cooperation with unknown factors, although it is unclear at present whether or not calmodulin is a candidate for such a factor.In conclusion, we propose that zymosan may stimulate iPLA2-mediated AA liberation, probably through PKC-dependent iPLA2 translocation to the membranes. Thus, the present work appears to provide one of the aspects concerning the role and regulation of group VI iPLA2 upon stimulation. The liberation of arachidonic acid (AA)1 upon stimulation is an important event leading to the generation of biologically active lipid mediators, such as prostaglandins and leukotrienes, and is mainly dependent on the hydrolysis of membrane glycerophospholipids catalyzed by phospholipase A2 (PLA2) (1van den Bosch H. Biochim. Biophys. Acta. 1980; 604: 191-246Crossref PubMed Scopus (826) Google Scholar, 2Waite M. J. Lipid Res. 1985; 26: 1379-1388Abstract Full Text PDF PubMed Google Scholar). Numerous types of mammalian PLA2s have been identified and classified into several groups (3Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). The mammalian PLA2s include at least two types of intracellular PLA2s,i.e. Ca2+-dependent and -independent enzymes. It is widely accepted that the intracellular PLA2 responsible for stimulus-induced AA liberation is group IV Ca2+-dependent cytosolic PLA2 (cPLA2), which preferentially hydrolyzes glycerophospholipids with an arachidonoyl residue at thesn-2 position (4Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 1170: 217-231Crossref PubMed Scopus (371) Google Scholar, 5Leslie C.C. J. Biol. Chem. 1997; 272: 16709-16712Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar). The activation of cPLA2upon stimulation is mediated by Ca2+-dependent translocation to membranes (6Channon J.Y. Leslie C.C. J. Biol. Chem. 1990; 265: 5409-5413Abstract Full Text PDF PubMed Google Scholar, 7Glover S. Bayburt T. Jonas M. Chi E. Gelb M.H. J. Biol. Chem. 1995; 270: 15359-15367Crossref PubMed Scopus (314) Google Scholar), and by mitogen-activated protein kinase-catalyzed phosphorylation (8Lin L.-L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. Davis R.J. Cell. 1993; 72: 269-278Abstract Full Text PDF PubMed Scopus (1643) Google Scholar, 9Nemenoff R.A. Winitz S. Qian N.-X. Putten V.V. Johnson G.L. Heasley L.E. J. Biol. Chem. 1993; 268: 1960-1964Abstract Full Text PDF PubMed Google Scholar). On the other hand, Ca2+-independent PLA2 (iPLA2) has been detected in a variety of cells and tissues (reviewed in Ref. 10Ackermann E.J. Dennis E.A. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar). Among several types of iPLA2s, which have been purified, sequenced, and well characterized (11Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar, 12Tang J. Kriz R.W. Wolfman N. Shaffer M. Seehra J. Jones S.S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 13Balboa M.A. Balsinde J. Jones S.S. Dennis E.A. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 14Ma Z. Ramanadham S. Kempe K. Chi X.S. Ladenson J. Turk J. J. Biol. Chem. 1997; 272: 11118-11127Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 15Larsson P.K.A. Claesson H.E. Kennedy B.P. J. Biol. Chem. 1998; 273: 207-214Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), group VI iPLA2in mouse macrophage-like P388D1 cells has been proposed to participate in phospholipid remodeling rather than stimulus-induced AA liberation (16Balsinde J. Bianco I.D. Ackermann E.J. Conde-Frieboes K. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8527-8531Crossref PubMed Scopus (255) Google Scholar, 17Balsinde J. Dennis E.A. J. Biol. Chem. 1997; 272: 16069-16072Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). 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