Abstract
In this study we investigated the effects of different agents known as activators or inhibitors of the calcium and phospholipid-dependent protein kinase (PKC) on the eicosanoid production in resident mouse peritoneal macrophages and in the murine macrophage-like cell line HA38. PKC activators such as the phorbol ester 12-O-tetradecanoyl 13-acetate (TPA) or the synthetic cell-permeable diacylglycerols 1,2-dioctanoylglycerol (DiC8) and 1-oleoyl-2-acetylglycerol (OAG) stimulated arachidonic acid (AA) release from prelabelled cells and also decreased AA incorporation into cellular phospholipids within minutes. This rapid enlargement in the amount of free AA available for eicosanoid synthesis resulted in a significantly enhanced cellular prostaglandin E2 (PGE2) production, whereas leukotriene C4 (LTC4) could not be detected under these experimental conditions. Increasing the intracellular calcium level by simultaneous addition of calcium ionophores together with PKC activators in suboptimal concentrations led to a synergistic production of PGE2 and LTC4. PKC inhibitors such as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), sphingosine, tamoxifen, and staurosporine, which exert their inhibitory action on PKC by different mechanisms, totally abolished TPA effects, whereas changes induced by (DiC8) or OAG were only partially reversed. Aluminum fluoride (AlF4 −) as an activator of regulatory guanine nucleotide binding proteins (G-proteins) elevated the intracellular concentration of inositolphosphates (IP) and diacylglycerols (DAG), thus leading to an activation of PKC and an increase in the intracellular calcium level, and subsequent enhanced eicosanoid production. AlF4 −-mediated PGEz and LTC4 synthesis again was reversed by using PKC inhibitors. Preincubation of the cells with pertussis toxin (PT) did not inhibit but even enhanced PGE2 production stimulated by zymosan or AlF4 −. Depletion of PKC activity by prolonged incubation of macrophages with TPA resulted in an extensive abrogation of the A1F4 − or zymosan-induced PGE2 secretion. These data provide further evidence that PKC is centrally involved in the regulation of macrophage eicosanoid synthesis initiated by different stimuli.
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References
Ase, K., Berry, N., Kikkawa, U., Kishimoto, A., and Nishizuka, Y., 1988, Differential down-regulation of protein kinase C subspecies in KM3 cells, FEBS Lett., 26:396.
Berridge, M.J., 1984, Inositol trisphosphate and diacyl-glycerol as second messengers, Biochem. J., 220:345.
Brune, K., Glatt, M., Kälin, H., and Peskar, B.A., 1978, Pharmacological control of prostaglandin and thromboxane release from macrophages, Nature, 274:261.
Burch, R.M., and Axelrod, J., 1987, A GTP-binding protein (G-protein) regulates phospholipase A2 in RAW264.7 macrophages, Fed. Proc., 46:703.
Cockcroft, S., 1987, Polyphosphoinositide phosphodiesterase: regulation by a novel guanine nucleotide binding protein, GP, TIPS, 12:75.
Emilsson, A., Wijkander, J., and Sundler, R., 1986, Diacyl-glycerol induces deacylation of phosphatidylinositol and mobilization of arachidonic acid in mouse macrophages, Biochem. J., 239:685.
Goppelt-Strübe, M., Pfannkuche, H.-J., Gemsa, D., and Resch, K., 1987, The diacylglycerols dioctanoylglycerol and oleoylacetylglycerol enhance prostaglandin synthesis by inhibition of the lysophosphatide acyltransferase, Biochem. J., 247:773.
Hamilton, T.A., and Adams, D.O., 1987, Molecular mechanisms of signal transduction in macrophages, Immunology Today, 8:151.
Hartung, H.P., Bitter-Suermann, D., and Hadding, U., 1983, Induction of thromboxane release from macrophages by anaphylatoxic peptide C3a of complement and synthetic hexapeptide C3a 72–77, J. Immunol., 130:1345.
Hill, E.E., and Lands, W.E.M., 1968, Incorporation of long-chain and polyunsaturated acids into phosphatidate and phosphatidylcholine, Biochim. Biophys. Acta, 152:645.
Irvine, R.F., 1982, How is the level of free arachidonic acid controlled in mammalian cells?, Biochem. J., 204:3.
Kaever, V., Firla, U., and Resch, K., 1988a, Sulfhydryl reagents as model substances for eicosanoid research, Eicosanoids, 1:49.
Kaever, V., Goppelt-Strübe, M., and Resch, K., 1988b, Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal, Prostaglandins, 35:885.
Kaever, V., Pfannkuche, H.-J., Wessel, K., and Resch, K., 1989, Regulation of eicosanoid synthesis in mouse peritoneal macrophages by protein kinase C, Agents Actions, 26:175.
Laemmli, U., 1970, Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature, 227:680.
Leslie, C.C., and Detty, D.M., 1986, Arachidonic acid turnover in response to lipopolysaccharide and opsonized zymosan in human monocyte-derived macrophages, Biochem. 236:251.
Moss, J., Horn, B.E., Hewlett, E.L., Tsai, S., Adamik, R., Halpern, J.L., Price, S.R., and Manganiello, V.C., 1988, Mechanism of enhanced sensitivity to bradykinin in pertussis toxin-treated fibroblasts: toxin increases bradykinin-stimulated prostaglandin formation, Mol. Pharmacol., 34:279.
Nishizuka, Y., 1988, The molecular heterogeneity of protein kinase C and its implication for cellular regulation, Nature, 334:661.
Ohno, S., Akita, Y., Konno, Y., Imajoh, S., and Suzuki, K., 1988, A novel phorbol ester receptor/protein kinase, nPKC, distantly related to the protein kinase C family, Cell, 53:731.
Pfannkuche, H.-J., Kaever, V., and Resch, K., 1986, A possible role of protein kinase C in regulating prostaglandin synthesis of mouse peritoneal macrophages, Biochem. Biophys. Res. Commun., 139:604.
Pfannkuche. H.-J., Kaever, V., Gemsa, D., and Resch, K., 1989, Regulation of prostaglandin synthesis by protein kinase C in mouse peritoneal macrophages, Biochem. J., 260:in press.
Scott, W.A., Pawlowski, N.A., Andreach, M., and Cohn, Z.A., 1982, Resting macrophages produce distinct metabolites from exogenous arachidonic acid, J. Exp. Med., 155:535.
Scott, W.A., Rouzer, C.A., and Cohn, Z.A., 1983, Leukotriene C4 release by macrophages, Fed. Proc., 42:129.
Uhing, R.J., and Adams, D.O., 1989, Molecular events in the activation of murine macrophages, Agents Actions, 26:9.
Verghese, M.W., Smith, C.D., Charles, L.A., Jakoi, L., and Snyderman, R., 1986, A guanine nucleotide regulatory protein controls polyphosphoinositide metabolism, Ca2+ mobilization, and cellular responses to chemoattractants in human monocytes, J. Immunol., 137:271.
Wessel, K., Kaever, V., Ostertag, W., Bitter-Suermann, D., and Resch, K., 1989, A virus-transformed macrophage-like cell line as tool for eicosanoid research, J. Leukocyte Biol., in press.
Wijkander, J., and Sundler, R., 1989, A role for protein kinase C-mediated phosphorylation in the mobilization of arachidonic acid in mouse macrophages, Biochim. Biophys. Acta, 1010:78.
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© 1990 Plenum Press, New York
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Kaever, V., Pfannkuche, HJ., Wessel, K., Sommermeyer, H., Resch, K. (1990). Eicosanoid Synthesis in Resident Macrophages: Role of Protein Kinase C. In: Vanderhoek, J.Y. (eds) Biology of Cellular Transducing Signals. GWUMC Department of Biochemistry Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0559-0_37
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DOI: https://doi.org/10.1007/978-1-4613-0559-0_37
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