* College of Veterinary Medicine, The University of Tennessee, 2407 River Drive. Knoxville, Tennessee 37996-4500; and
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
Received April 7, 1999; accepted August 15, 1999
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ABSTRACT |
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Key Words: arachidonic acid; phospholipase A2; organochlorine compounds; neutrophils; superoxide anion; NADPH oxidase.
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INTRODUCTION |
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Our laboratory research has focused on the mechanism by which a related group of compounds, the PCBs, causes ROS formation in neutrophils (Ganey et al., 1993; Tithof et al., 1995
, 1996
, 1997
, 1998
). Activation of neutrophils by PCBs is complex and involves multiple enzymes including protein tyrosine kinases (Tithof et al., 1997
), phospholipase C (Tithof et al., 1995
), and phospholipase A2 (Tithof et al., 1996
). Activation of phospholipase A2 (PLA2) by PCBs results in the release of large amounts of arachidonic acid (AA), which is essential for activation of the O
-generating NADPH oxidase (Tithof et al., 1996
, 1998
). More recently, we have focused on characterization of the PLA2 that is activated by PCBs (Tithof et al., 1998
).
Several different isoforms of PLA2 have been described. These include a large-molecular-weight cytosolic PLA2, which is calcium-dependent and selective for arachidonic acid at the sn-2 position of phospholipids (Alonso et al., 1986; Gronich et al., 1988
; Kramer et al., 1991
) and small-molecular-weight, calcium-dependent enzymes that are arachidonoyl-nonselective (14 kDa secretory PLA2 and 14 kDa pancreatic PLA2) (Dennis et al., 1991
; Mayer and Marshall, 1993
). In addition, a number of PLA2 enzymes have been described which are activated by a mechanism that does not require calcium. These include a calcium-independent enzyme found in cardiac myocytes, which is selective for arachidonic acid (Hazen et al., 1991b
), and an enzyme in macrophage-like p388D1 cells which is not (Ackermann et al., 1994
).
Recently, we demonstrated that the PLA2 activated by PCBs is an isoform not previously described in neutrophils (Tithof et al., 1998). Specifically, the enzyme is activated in the absence of calcium, is selective for arachidonate at the sn-2 position, and is inhibited by bromoenol lactone (BEL), an agent that is selective for calcium-independent PLA2 isoforms (Hazen et al., 1991b
). Activation of this PLA2 isoform may play an important role in the mechanism by which other chlorinated compounds cause ROS formation. Therefore, the purpose of the present study was to test the hypothesis that dieldrin and lindane stimulate O
production in neutrophils by a mechanism that involves calcium-independent PLA2.
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MATERIALS AND METHODS |
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Neutrophil isolation.
Glycogen-elicited neutrophils were obtained from the peritoneal cavity of male Sprague-Dawley, retired-breeder rats as described previously (Ganey et al., 1993). Rats were anesthetized with diethyl ether, and were injected intraperitoneally with 30 ml of 1% glycogen. After 4 h, the rats were anesthetized again and killed by decapitation. The peritoneal cavity was washed with 30 ml of heparinized (1 U/ml) 0.1 M phosphate-buffered saline (PBS). The solution obtained from the peritoneal cavity was collected, filtered through gauze, and centrifuged at 500 x g for 7 min. Contaminating red blood cells were lysed with 15 ml of 0.15 M NH4Cl, and neutrophils were suspended to a final volume of 50 ml with PBS and centrifuged for 7 min at 300 x g. Cells were washed once with 0.1 M PBS and resuspended in Hanks' balanced salt solution (HBSS).
Labeling of neutrophils with 3H-arachidonic acid.
Neutrophils were suspended in Ca2+- and Mg2+-free HBSS containing 0.1% bovine serum albumin (BSA) and were labeled for 90 min at 37°C with 0.5 µCi/ml 3H-arachidonic acid (3H-AA). Suspended neutrophils were prelabeled in the absence of Ca2+ and Mg2+ to prevent cellular aggregation. At the end of the labeling period, neutrophils were washed x2 and resuspended in HBSS containing 0.1% BSA, according to the method of Volpi et al., (1984). At the end of the incubation period, an aliquot of cells was subjected to scintillation counting to determine cellular uptake of radiolabel: uptake was routinely ~70% of added 3H-AA. In addition, the distribution of label within the various phospholipids was determined by thin-layer chromatography. Approximately 22% was distributed into phosphatidylinositol, 8% into phosphatidylserine, 53% into phosphatidylcholine, and 17% into phosphatidylethanol, indicating uniform distribution of label amongst membrane phospholipids. At the end of the labeling period, neutrophils were washed x2 and resuspended in HBSS containing 0.1% BSA.
Determination of fatty acid release from prelabeled neutrophils.
Cumulative release of 3H-AA was measured in cells stimulated for 20 min at 37°C with various concentrations of lindane (0, 10, 25, 50, and 100 µM) or dieldrin (0, 1, 10, 25, 50, and 100 µM). To determine the kinetics of release of arachidonate, accumulation of 3H-AA in the medium was determined in neutrophils stimulated for various times (1, 5, 10, or 30 min) with lindane (100 µM) or dieldrin (100 µM). To determine the role of calcium-independent PLA2 in lindane- and dieldrin-induced release of AA, neutrophils were preincubated for 15 min with the inhibitor of calcium-independent PLA2, BEL (0.120 µM). This was followed by stimulation with lindane or dieldrin for 20 min. Neutrophils were stimulated with lindane or dieldrin for 20 min in the presence or absence of extracellular calcium, and in the presence of 0.5 mM EGTA, to determine the role of extracellular calcium in stimulated release of AA. To determine the role of intracellular calcium in release of AA, neutrophils were loaded with the cell-permeant calcium chelator BAPTA-AM (50 µM) in calcium-free medium for 60 min prior to stimulation. This concentration of BAPTA-AM has been shown previously to effectively chelate intracellular calcium in neutrophils (O'Flaherty et al., 1991). At the end of the incubations, neutrophils were placed on ice and centrifuged, and radioactivity in the cell-free supernatant fluids was determined by liquid scintillation counting.
Generation and detection of O.
Superoxide anion (O) production was measured in neutrophils stimulated as describe above. Cumulative O
production was measured as the reduction of cytochrome C in the presence or absence of superoxide dismutase (SOD) (Babior et al., 1973
). For every sample, two tubes were incubated, one to which SOD (840 U/ml) was added before stimulation and one to which SOD (840 U/ml) was added at the end of incubation. The amount of cytochrome C reduced was estimated from the difference in absorbance (550 nm) between the cell-free supernatant fluids in the two tubes, using an extinction coefficient of 18.5 cm-1mM-1.
Determination of cytotoxicity.
Cytotoxicity was determined in neutrophils exposed to dieldrin or lindane by measuring activity of the cytosolic enzyme, lactate dehydrogenase (LDH), in cell-free supernatant fluids as described previously (Tithof et al., 1995).
Statistical analysis.
Data are expressed as mean ± SEM. Data were analyzed by analysis of variance, and group means were compared using Student-Newman-Keuls' test. Appropriate transformations were performed on all data that did not follow a normal distribution (e.g., percent data). If transformation failed to normalize the data, nonparametric statistics (Mann-Whitney rank sum test) were used. For all studies, the criterion for statistical significance was p < 0.05.
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RESULTS |
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DISCUSSION |
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One PLA2 isoform activated upon exposure of neutrophils to lindane or dieldrin is likely to be the same as, or similar to the calcium-independent enzyme that is activated by PCBs (Tithof et al., 1998). Evidence for this conclusion is based on the findings that lindane and dieldrin caused the release of AA in the presence of calcium-free medium and in cells loaded with the intracellular calcium chelator, BAPTA-AM (Fig. 3
). In cells stimulated with lindane, AA release was not significantly different in the presence or absence of calcium, suggesting that the predominant isoform of PLA2 activated by lindane in rat neutrophils is a calcium-independent isoform. Lindane-induced inhibition of gap junctional intercellular communication in rat, myometrial smooth muscle cells is dependent on release of AA and is not inhibited by removal of extracellular calcium, thus indirectly implicating activation of a calcium-independent PLA2 in that system as well (Criswell and Loch-Caruso, 1995
; Criswell et al., 1995
). Although omission of extracellular calcium did not cause a significant decrease in release of AA, pretreatment with BEL, an agent that inhibits many calcium-independent isoforms of PLA2 with 1000-fold greater potency than its effect on calcium-dependent enzymes (Hazen et al., 1991b
), decreased AA release by only 56%. These results indicate that nearly half of the AA released arises from a calcium-independent mechanism other than BEL-sensitive PLA2. Several isoforms of calcium-independent PLA2 have been characterized that are not inhibited by BEL. These include acidic calcium-independent PLA2 isoforms isolated from lung and several other organs (Akiba et al., 1994
; Kim et al., 1998
), and a cytosolic isoform that is expressed in rat ventricular myocytes (Liu and McHowat, 1998
). Lindane may cause the release of AA by activating more than one isoform of calcium-independent PLA2 having different sensitivities to BEL. Alternatively, phospholipase D may be the source of the BEL-insensitive portion of the released AA. Activation of phospholipase D can occur in a calcium-independent manner (English et al., 1991
), and AA can be liberated from some phospholipids by this enzyme (Song and Foster, 1993
).
Dieldrin caused significant accumulation of arachidonate both in the presence and absence of calcium, but in contrast to lindane, the amount of AA released was significantly less under calcium-free conditions. In fact, less than 50% of the AA released in response to dieldrin could be attributed to calcium-independent phospholipase A2 activity. These results suggest that dieldrin activates more than one isoform of PLA2 that differ in their requirements for calcium. This conclusion is corroborated by results with BEL. Release of AA was inhibited only partially by either preincubation with BEL (40% inhibition at 20 µM) or by omission of extracellular calcium (51% inhibition), supporting the interpretation that both calcium-dependent and calcium-independent isoforms of PLA2 are involved.
Despite incomplete inhibition of AA release by BEL, this inhibitor nearly abolished O production in response to either lindane or dieldrin (Figs. 4 and 5
). There are several possible explanations for these results. One explanation is that both dieldrin and lindane activate more than one isoform of PLA2, and these enzymes release AA for different cellular functions. The portion of released AA that was inhibited by BEL may be required for activation of the NADPH oxidase, while the portion of released AA that was not inhibited by BEL may be linked to cellular functions other than generation of O
(e.g., eicosanoid production). Although eicosanoid production in response to lindane or dieldrin has not been reported for neutrophils, both agents have been shown to cause the release of eicosanoids from other cell types (Forgue et al., 1990
; Kacew and Singhal, 1974
). Furthermore, in neutrophils, two different PLA2 isoforms are responsible for O
generation and eicosanoid production. One PLA2 is a calcium-independent isoform that is activated by PCBs and causes the release of AA for activation of the NADPH oxidase. The other PLA2 isoform is a calcium-dependent enzyme that is activated by A23187 and results in the release of AA for subsequent production of prostaglandins and leukotrienes (Tithof et al., 1998
). Thus, BEL may totally abolish O
generation without completely inhibiting AA release by inhibiting only the isoform(s) of PLA2 that is (are) linked to NADPH oxidase activity.
An alternative explanation for the complete inhibition of O production, despite incomplete inhibition of AA release in the presence of BEL may lie in the mechanisms of BEL's action. Although BEL selectively inhibits calcium-independent isoforms among phospholipases A2, it does have other activity. At concentrations which inhibit calcium-independent PLA2, BEL also inhibits phosphatidic acid phosphohydrolase (PAP) (Balsinde and Dennis, 1996
), an enzyme that catalyzes the production of diacylglycerol from phosphatidic acid, which arises as a result of phospholipase D activation. Activation of PAP and phospholipase D has been implicated in the production of O
in neutrophils stimulated with phorbol myristate acetate (PMA) or f-met-leu-phe (fMLP) (English and Taylor, 1991
; Perry et al., 1992
). However, these conclusions were based solely on the findings that O
production was attenuated by the inhibitor of PAP, DL-propranolol. This inhibitor also demonstrated the ability to decrease the activity of protein kinase C (Sozzani et al., 1992
), an enzyme that is known conclusively not only to be targeted by fMLP and PMA (Castagna et al., 1982
; Nishizuka, 1984
), but also to play an essential role in the assembly and activation of the NADPH oxidase (Tauber, 1987
). Thus, interpretation of results, using propranolol to implicate PLD in a mechanism, is obscured by simultaneous inhibition of protein kinase C. Since most, if not all studies that suggest a role for PAP in production of O
have been based on the use of propranolol, it is improbable that BEL's action to inhibit O
production by neutrophils stimulated with dieldrin or lindane occurred through a mechanism involving this pathway (Sozzani et al., 1992
).
Although mobilization of AA for the generation of O occurs in a calcium-independent manner in neutrophils exposed to dieldrin or lindane, generation of O
does not. Omission of extracellular calcium reduces O
production in dieldrin-treated neutrophils by greater than 90% (Hewett and Roth, 1988
). Likewise, incubation with the intracellular calcium antagonist, TMB-8 (Kuhns et al., 1986
), or omission of calcium from the extracellular medium (English et al., 1986
) attenuates O
generation in lindane-treated neutrophils. These results suggest that the requirement for calcium may occur distal to PLA2 activation in the signal transduction pathway. Since arachidonic acid has been shown to act as a calcium ionophore (Ramanadham et al., 1993
; Soliven et al., 1993
), it is possible that PLA2-mediated AA release causes intracellular calcium to rise by mobilizing extracellular or intracellular stores.
Organochlorine pesticides have been shown to be potent neurotoxicants. These compounds exert their neurotoxicity by binding to the GABAA receptor-Cl- ionophore complex, which mediates inhibitory synaptic neurotransmission in the central nervous system (Ghiasuddin and Matsumura, 1982). Lindane has also been shown to alter calcium-channel activity, and this alteration has been implicated in the neurotoxicity (Rosa et al., 1997
), immunotoxicity (Meera et al., 1993
), and alterations in reproductive function (Criswell et al., 1994
) associated with this class of compound. The neural and reproductive effects occur in the nanomolar to micromolar range. However, the effects on the immune system occur at somewhat higher concentrations. For example, significant inhibition of gap junctional communication and release of 3H-AA from rat myometrium can be seen after exposure to 100 nM lindane (Criswell and Loch-Caruso, 1995
). However, significantly higher concentrations were required to cause O
production and 3H-AA release in phagocytic cells (Kuhns et al., 1986
). The concentrations used in this study and in previous in vitro studies (Kuhns et al., 1986
) are within the range shown to cause immunotoxicity in animal models (Koner et al., 1998
).
Calcium-independent PLA2 isoforms have been implicated in a variety of disease states in which oxidative stress has been implicated (Goligorsky et al., 1993; Hazen et al., 1991a
; Kuo et al., 1995
; McHowat et al., 1998
; Ross et al., 1997
). Since both dieldrin and lindane have been shown to cause parenchymal cell injury by inducing oxidative stress (Bachowski et al., 1997
; Junqueira et al., 1986
, 1994
), it is plausible that activation of calcium-independent PLA2 is involved in this process. This possibility warrants further investigation.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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Akiba, S., Dodia, C., Chen, X., and Fisher, A. B. (1994). Characterization of acidic Ca(2+)-independent phospholipase A2 of bovine lung. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 120, 393404.
Alonso, F., Henson, P. M, and Leslie, C. C. (1986). A cytosolic phospholipase in human neutrophils that hydrolyzes arachidonoyl-containing phosphatidylcholine. Biochim. Biophys. Acta 878, 273280.[ISI][Medline]
Babior, B. M., Kipnes, R. S., and Curnutte, J. T. (1973). Biological defense mechanisms: The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 52, 741744.[ISI][Medline]
Bachowski, S., Kolaja, K. L., Xu, Y., Ketcham, C. A., Stevenson, D. E., Walborg, E. F., and Klaunig, J. E. (1997). Role of oxidative stress in the mechanism of dieldrin's hepatotoxicity. Ann. Clin. Lab. Sci. 27, 196209.[Abstract]
Balsinde, J., and Dennis, E. A. (1996). Bromoenol lactone inhibits magnesium-dependent phosphatidate phosphohydrolase and blocks triacylglycerol biosynthesis in mouse P388D1 macrophages. J. Biol. Chem. 271, 3193731941.
Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y. (1982). Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257, 78477851.
Criswell, K. A., and Loch-Caruso, R. (1995). Lindane-induced elimination of gap junctional communication in rat uterine myocytes is mediated by an arachidonic acid-sensitive cAMP-independent mechanism. Toxicol. Appl. Pharmacol. 135, 127138.[ISI][Medline]
Criswell, K. A., Loch-Caruso, R., and Stuenkel, E. L. (1995). Lindane inhibition of gap junctional communication in myometrial myocytes is partially dependent on phosphoinositide-generated second messengers. Toxicol. Appl. Pharmacol. 130, 280293.[ISI][Medline]
Criswell, K. A., Stuenkel, E. L., and Loch-Caruso, R. (1994). Lindane increases intracellular calcium in rat myometrial smooth muscle cells through modulation of inositol 1,4,5-trisphosphate-sensitive stores. J. Pharmacol. Exp. Ther. 270, 10151024.[Abstract]
Dana, R., Malech, H. L., and Levy, R. (1994). The requirement for phospholipase A2 for activation of the assembled NADPH oxidase in human neutrophils. Biochem. J. 297, 217223.[ISI][Medline]
Dennis, E. A., Rhee, S. G., Billah, M. M., and Hannun, Y. A. (1991). Role of phospholipase in generating lipid second messengers in signal transduction. FASEB J. 5, 20682077.
English, D., Schell, M., Siakotos, A., and Gabig, T. G. (1986). Reversible activation of the neutrophil superoxide generating system by hexachlorocyclohexane: Correlation with effects on a subcellular superoxide-generating fraction. J. Immunol. 137, 283290.
English, D., and Taylor, G. S. (1991). Divergent effects of propranolol on neutrophil superoxide release: involvement of phosphatidic acid and diacylglycerol as second messengers. Biochem. Biophys. Res. Commun. 175, 423429.[ISI][Medline]
English, D., Taylor, G., and Garcia, J. G. (1991). Diacylglycerol generation in fluoride-treated neutrophils: involvement of phospholipase D. Blood 77, 27462756.[Abstract]
Forgue, M. F., Pinelli, E., Beraud, M., Souqual, M. C., and Pipy, B. (1990). Chemiluminescence response and arachidonic acid metabolism of macrophages induced by gamma-hexachlorocyclohexane (lindane). Food Addit. Contam. 7(Suppl. 1), S97S99.
Ganey, P. E., Sirois, J. E., Denison, M., Robinson, J. P., and Roth, R. A. (1993). Neutrophil function after exposure to polychlorinated biphenyls in vitro. Environ. Health Perspect. 101, 430434.[ISI][Medline]
Ghiasuddin, S. M., and Matsumura, F. (1982). Inhibition of gamma-aminobutryic acid (GABA)-induced chloride uptake by gamma-BHC and heptachlor epoxide. Comp Biochem. Physiol. 73C, 141144.[ISI]
Goligorsky, M. S., Morgan, M. A., Lyubsky, S., Gross, R. W., Adams, D. T., and Spitz, D. R. (1993). Establishment of a hydrogen peroxide-resistant variant of renal tubular epithelial cells: Role of calcium-independent phospholipase A2 in cell damage. Arch. Biochem. Biophys. 301, 119128.[ISI][Medline]
Gronich, J., Bonventre, J., and Nemenoff, R. (1988). Identification and characterization of a hormonally regulated form of phospholipase A2 in rat renal mesangial cells. J. Biol. Chem. 263, 1664516651.
Hazen, S. L., Ford, D. A., and Gross, R. W. (1991a). Activation of a membrane-associated phospholipase A2 during rabbit myocardial ischemia which is highly selective for plasmologen substrate. J. Biol. Chem. 266, 56295633.
Hazen, S. L., Zupan, L. A., Weiss, R. H., Getman, D. P., and Gross, R. W. (1991b). Suicide inhibition of canine myocardial cytosolic calcium-independent phosholipase A2: Mechanism-based discrimination between calcium-dependent and -independent phospholipases A2. J. Biol. Chem. 266, 72277232.
Henderson, L. M., Banting, G., and Chappell, J. B. (1995). The arachidonate-activatable, NADPH oxidase-associated H+ channel: evidence that gp91-phox functions as an essential part of the channel. J. Biol. Chem. 270, 59095916.
Henderson, L. M., Moule, S. K., and Chappell, J. B. (1993). The immediate activator of the NADPH oxidase is arachidonate not phosphorylation. Eur. J. Biochem. 211, 157162.[Abstract]
Hewett, J. A., and Roth, R. A. (1988). Dieldrin activates rat neutrophils in vitro. Toxicol. Appl. Pharmacol. 96, 269278.[ISI][Medline]
Junqueira, V. B., Bainy, A. C., Arisi, A. C., Azzalis, L. A., Simizu, K., Pimentel, R., Barros, S. B., and Videla, L. A. (1994). Acute lindane intoxication: a study on lindane tissue concentration and oxidative stress-related parameters in liver and erythrocytes. J. Biochem. Toxicol. 9, 915.[ISI][Medline]
Junqueira, V. B., Simizu, K., Videla, L. A., and Barros, S. B. (1986). Dose-dependent study of the effects of acute lindane administration on rat liver superoxide anion production, antioxidant enzyme activities, and lipid peroxidation. Toxicology 41, 193204.[ISI][Medline]
Kacew, S., and Singhal, R. L. (1974). Effect of certain halogenated hydrocarbon insecticides on cyclic adenosine 3',5'-monophosphate-3H formation by rat kidney cortex. J. Pharmacol. Exp. Ther. 188, 265276.[ISI][Medline]
Kim, T. S., Dodia, C., Chen, X., Hennigan, B. B., Jain, M., Feinstein, S. I., and Fisher, A. B. (1998). Cloning and expression of rat lung acidic Ca(2+)-independent PLA2 and its organ distribution. Am. J. Physiol. 274, L750L761.
Klaunig, J. E., Xu, Y., Bachowski, S., Ketcham, C. A., Isenberg, J. S., Kolaja, K. L., Baker, T. K., Walborg, E. F., and Stevenson, D. E. (1995). Oxidative stress in nongenotoxic carcinogenesis. Toxicol. Lett. 8283, 683691.
Klaunig, J. E., Xu, Y., Isenberg, J. S., Bachowski, S., Kolaja, K. L., Jiang, J., Stevenson, D. E., and Walborg, E. F. (1998). The role of oxidative stress in chemical carcinogenesis. Environ. Health Perspect. 106(Suppl. 1), 289295.
Koner, B. C., Banerjee, B. D., and Ray, A. (1998). Organochlorine pesticide-induced oxidative stress and immune suppression in rats. Indian J. Exp. Biol. 36, 395398.[Medline]
Kramer, R., Roberts, E., Manetta, J., and Putnam, J. (1991). The calcium-sensitive cytosolic phospholipase A2 is a 100-kDa protein in human monoblast U937 cells. J. Biol. Chem. 266, 52685272.
Kuhns, D. B., Kaplan, S. S., and Basford, R. E. (1986). Hexachlorocyclohexanes, potent stimuli of O2 production and calcium release in human polymorphonuclear leukocytes. Blood 68, 535540.
Kuo, C. F., Cheng, S., and Burgess, J. R. (1995). Deficiency of vitamin E and selenium enhances calcium-independent phospholipase A2 activity in rat lung and liver. J. Nutr. 125, 14191429.[ISI][Medline]
Liu, S. J., and McHowat, J. (1998). Stimulation of different phospholipase A2 isoforms by TNF-alpha and IL-beta in adult rat ventricular myocytes. Am. J. Physiol. 275, H1462H1472.
Mayer, R. J., and Marshall, L. A. (1993). New insights on mammalian phospholipase A2(s): Comparison of arachidonoyl-selective and -nonselective enzymes. FASEB J. 7, 339348.
McHowat, J., Liu, S., and Creer, M. H. (1998). Selective hydrolysis of plasmologen phospholipids by Ca2+-independent PLA2 in hypoxic ventricular myocytes. Am. J. Physiol. 274, C1727C1737.
Meade, C. J., Harvey, J., Boot, J. R., Turner, G. A., Bateman, P. E., and Osborne, D. J. (1984). Gamma-hexachlorocyclohexane stimulation of macrophage phospholipid hydrolysis and leukotriene production. Biochem. Pharmacol. 33, 289293.[ISI][Medline]
Meera, P., Tripathi, O., Kamboj, K. K., and Rao, P. R. (1993). Role of calcium in biphasic immunomodulation by gamma-HCH (lindane) in mice. Immunopharm. Immunotox. 15, 113129.[ISI][Medline]
Nishizuka, Y. (1984). The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308(5961), 693698.[ISI][Medline]
O'Flaherty, J. T., Rossi A. G., Jacobson D. P., and Redman J. F. (1991). Roles of Ca2+ in human neutrophil responses to receptor agonists. Biochem. J. 278, 705711.[ISI][Medline]
Perry, D. K., Hand, W. L., Edmondson, D. E., and Lambeth, J. D. (1992). Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors. J. Immunol. 149, 27492758.
Puente-Fraga, J. C., Lopez-Aparicio, P., Senar, S., Recio, M. N., and Perez-Albarsanz, M. A. (1995). Hexachlorocyclohexanes affect the arachidonic acid release from phosphatidylinositol but not from other phospholipid classes in tubular cell cultures. Biosci. Rep. 15, 191199.[ISI][Medline]
Ramanadham, S., Gross, R. W., Han, X., and Turk, J. (1993). Inhibition of arachidonate release by secretagogue-stimulated pancreatic islets suppresses both insulin secretion and the rise in beta-cell cytosolic calcium ion concentration. Biochemistry 21, 337346.
Rosa, R., Sanfeliu, C., Sunol, C., Pomes, A., Rodriguez-Farre, E., Schousboe, A., and Frandsen, A. (1997). The mechanism for hexachlorocyclohexane-induced cytotoxicity and changes in Ca2+ homeostasis in cultured cerebellar granule neurons is different for the gamma- and delta-isomers. Toxicol. Appl. Pharmacol. 142, 3139.[ISI][Medline]
Ross, B. M., Hudson, C., Erlich, J., Warsh, J. J., and Kish, S. J. (1997). Increased phospholipid breakdown in schizophrenia: Evidence for the involvement of a calcium-independent phospholipase A2. Arch. Gen. Psychiatry 54, 487494.[Abstract]
Soliven, B., Takeda, T., Shandy, T., and Nelson, D. (1993). Arachidonic acid and its metabolites increase Ca(I) in cultured rat oligodendrocytes. Am. J. Physiol. 264, C632C640.
Song, J., and Foster, D. A. (1993). v-Src activates a unique phospholipase D activity that can be distinguished from the phospholipase D activity activated by phorbol esters. Biochem. J. 294, 711717.[ISI][Medline]
Sozzani, S., Agwu, D. E., McCall, C. E., O'Flaherty, J. T., Schmitt, J. D., Kent, J. D., and McPhail, L. C. (1992). Propranolol, a phosphatidate phosphohydrolase inhibitor, also inhibits protein kinase C. J. Biol. Chem. 267, 2048120488.
Tauber, A. I. (1987). Protein kinase C and the activation of the human neutrophil NADPH-oxidase. Blood 69, 711720.[ISI][Medline]
Tithof, P. K., Contreras, M. L., and Ganey, P. E. (1995). Aroclor 1242 stimulates the production of inositol phosphates in polymorphonuclear neutrophils. Toxicol. Appl. Pharmacol. 131, 136143.[ISI][Medline]
Tithof, P. K., Peters-Golden, M., and Ganey, P. E. (1998). Distinct phospholipases A2 regulate the release of arachidonic acid for eicosanoid production and superoxide anion generation in neutrophils. J. Immunol. 160, 953960.
Tithof, P. K., Schiamberg, E., Peters-Golden, M., and Ganey, P. E. (1996). Phospholipase A2 is involved in the mechanism of activation of neutrophils by polychlorinated biphenyls. Environ. Health Perspect. 104, 5258.[ISI][Medline]
Tithof, P. K., Watts, S., and Ganey, P. E. (1997). Protein tyrosine kinase involvement in the production of superoxide anion by neutrophils exposed to Aroclor 1242, a mixture of polychlorinated biphenyls. Biochem. Pharmacol. 53, 18331842.[ISI][Medline]
Volpi M., Yassin R., Tao W., Molski T. F., Naccacche P. H., and Sha'afi R. I. (1984). Luekotriene B4 mobilizes calcium without the breakdown of polyphosphoinositides and the production of phosphatidic acid in rabbit neutrophils. Proc. Natl. Acad. Sci. U S A 81, 59665969.[Abstract]