Skip to main content
NCBI home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 2003 Mar 7;613(1):67–73. doi: 10.1016/0006-8993(93)90455-V

Regulation of astrocyte proliferation by prostaglandin E2 and the α subtype of protein kinase C

Makoto Sawada a,**, Akio Suzumura b, Kazushige Ohno a,*, Tohru Marunouchi a
PMCID: PMC7111161  PMID: 8348305

Abstract

We found that astrocytes expressed the α subtype of protein kinase C. Treatment with12-O-tetradecanoylphorbol 13-acetate (TPA) caused cultured astrocytes to proliferate. This effect of TPA was blocked by staurosporine, a potent protein kinase C inhibitor, suggesting the involvement of protein kinase C in astrocyte proliferation. Indomethacin, an inhibitor of prostaglandin formation, enhanced both the normal and TPA-induced proliferation of astrocytes. Authentic prostaglandin E2 blocked this effect of indomethacin and also partially blocked the effect of TPA, suggesting that the intracellular mechanisms involved in prostaglandin E2-regulated astrocyte growth might differ from those acting in protein kinase-dependent growth. The effect of prostaglandin E2 was blocked by a specific anti-prostaglandin E2 polyclonal antibody. Cultured astrocytes and microglia produced and released prostaglandin E2 in response to stimulants such as lipopolysaccharide, TPA, and lymphokines. Since the sensitivity of astrocytes and microglia to these stimuli was different, prostaglandin E2 may differentially regulate astrocyte proliferation under different physiological conditions, acting in an autocrine fashion for astrocytes and in a paracrine fashion for microglia.

Keywords: Astrocyte growth regulation, Prostaglandin, α-Subtype of protein kinase C, 12-O-Tetradecanolyphorbol 13-acetate, Brain cell culture

Keywords: GFAP glial fibrillary acidic protein; LPS lipopolysaccharide; MTT 3-[4,5-demethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; TPA 12-O-tetradecanolyphorbol 13-acetate

References

  • 1.Berridge M.J. Intracellular signaling through inositol tris-phosphate and diacylglycerol. Biol. Chem. Hoppe-Seyler. 1986;367:447–456. [PubMed] [Google Scholar]
  • 2.Bhat N.R. Role of protein kinase C in glial cell proliferation. J. Neurosci. Res. 1989;22:20–27. doi: 10.1002/jnr.490220104. [DOI] [PubMed] [Google Scholar]
  • 3.Bolton C., Gordon D., Turk J.L. A longitudinal study of the prostaglandin content of central nervous system tissues from guinea pigs with acute experimental allergic encephalomyelitis. Int. J. Immunopharmacol. 1984;6:155–161. doi: 10.1016/0192-0561(84)90011-0. [DOI] [PubMed] [Google Scholar]
  • 4.Burch R.M., Kniss D.A. Modulation of receptor-mediated signal transduction by diacylglycerol mimetics in astrocytes. Cell. Moll. Neurobiol. 1988;8:251–257. doi: 10.1007/BF00711251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Coussens L., Parker P.J., Rhee L., Yang-Feng T.L., Chen E., Waterfield M.D., Francke U., Ullrich A. Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. Science. 1986;233:859–866. doi: 10.1126/science.3755548. [DOI] [PubMed] [Google Scholar]
  • 6.Fierz W., Endler B., Reske K., Wekerle H., Fontana A. Astrocytes as antigen-presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effects on antigen presentation. J. Immunol. 1985;134:3785–3793. [PubMed] [Google Scholar]
  • 7.Frei K., Malipiero U.V., Leist T.P., Zinkernagel R.M., Schwab M.E., Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 1989;19:689–694. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  • 8.Fontana A., Kristensen F., Dubs R., Gemsa D., Weber E. Production of prostaglandin E and an interleukin-1 like factor by cultured astrocyte and C6 glioma cells. J. Immunol. 1982;129:2413–2419. [PubMed] [Google Scholar]
  • 9.Gemsa D. Stimulation of prostaglandin E release from macrophages and possible roles in the immune response. Lymphokines. 1981;4:335–375. [Google Scholar]
  • 10.Girard P.R., Mazzei G.J., Wood J.G., Kuo J.F. 2nd edn. Vol. 82. 1985. Polyclonal antibodies to phospholipid/Ca2+-dependent protein kinase and immunocytochemical localization of the enzyme in rat brain; pp. 3030–3034. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Giulian D., Baker T.J., Shih L.-C.N., Lachman L.B. Interleukin-1 of the central nervous system is produced by ameboid microglia. J. Exp. Med. 1986;164:594–604. doi: 10.1084/jem.164.2.594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Goldyne M.E., Stobo J.D. Immunoregulatory role of prostaglandins and related lipids. CRC Crit. Rev. Immunol. 1981;2:189–223. [Google Scholar]
  • 13.Goodwin J.S., Webb D.R. Regulation of the immune response by prostaglandins. Clin. Immunol. Immunopathol. 1980;15:106–122. doi: 10.1016/0090-1229(80)90024-0. [DOI] [PubMed] [Google Scholar]
  • 14.Hartung H.-P., Toyka K.V. Phorbol diester TPA elicits prostaglandin E release from cultured rat astrocytes. Brain Res. 1987;417:347–349. doi: 10.1016/0006-8993(87)90461-6. [DOI] [PubMed] [Google Scholar]
  • 15.Kikkawa U., Takai Y., Minakuchi R., Inohara S., Nishizuka Y. Calcium-activated, phospholipid-dependent protein kinase from rat brain: subcellular distribution, purification and properties. J. Biol. Chem. 1982;257:13341–13348. [PubMed] [Google Scholar]
  • 16.Knopf J.L., Lee M.-H., Sultzman L.A., Kriz R.W., Loomis C.R., Hewick R.M., Bell R.M. Cloning and expression of multiple protein kinase C cDNAs. Cell. 1986;46:491–502. doi: 10.1016/0092-8674(86)90874-3. [DOI] [PubMed] [Google Scholar]
  • 17.Korr H. Proliferation of different cell types in the brain. In: Brodal A., Hild W., van Limbrough J., Ortman R., Schiebler T.H., Tondury G., Wolff E., editors. Advances in Anatomy, Embryology and Cell Biology. Springer-Verlag; New York: 1980. pp. 5–16. [DOI] [PubMed] [Google Scholar]
  • 18.Makowske M., Birnbaum M.J., Ballester R., Rosen O.M. A cDNA encoding protein kinase C identifies two species of mRNA in brain and GH3 cells. J. Biol. Chem. 1986;261:13389–13392. [PubMed] [Google Scholar]
  • 19.Malipiero U.V., Frei K., Fontana A. Production of hemopoietic colony-stimulating factors by astrocytes. J. Immunol. 1990;144:3816–3821. [PubMed] [Google Scholar]
  • 20.Merrill J.E. Macroglia: neural cells responsive to lymphokines and growth factors. Immunol. Today. 1987;8:146–150. doi: 10.1016/0167-5699(87)90144-7. [DOI] [PubMed] [Google Scholar]
  • 21.Merrill J.E., Gerner R.H., Myers L.W., Ellison G.W. Regulation of natural killer cell cytotoxicity by prostaglandin E in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J. Neuroimmunol. 1983;4:223–237. doi: 10.1016/0165-5728(83)90037-1. [DOI] [PubMed] [Google Scholar]
  • 22.Miller R.H., Abney E.R., David S., Ffrench-Constnat C., Lindsay R., Patel R., Stone J., Raff M.C. Is reactive gliosis a property of a distinct subpopulation of astrocytes? J. Neurosci. 1986;6:22–29. doi: 10.1523/JNEUROSCI.06-01-00022.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Minakuchi R., Takai Y., Yu B., Nishizuka Y. Wide-spread occurrence of calcium-activated, phospholipid-dependent protein kinase in mammalian tissues. J. Biochem. 1981;89:1651–1654. doi: 10.1093/oxfordjournals.jbchem.a133362. [DOI] [PubMed] [Google Scholar]
  • 24.Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983;65:55–58. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  • 25.Murphy K.M.M., Gould R.J., Oster-Granite M.L., Gerhart J.D., Snyder S.H. Phorbol ester receptors: autoradiographic identification in the developing rat. Science. 1983;222:1036–1038. doi: 10.1126/science.6316499. [DOI] [PubMed] [Google Scholar]
  • 26.Neary J.T., Norenberg L.O.B., Norenberg M.D. Calcium-activated, phospholipid-dependent protein kinase and protein substrates in primary culture of astrocytes. Brain Res. 1986;385:420–424. doi: 10.1016/0006-8993(86)91095-4. [DOI] [PubMed] [Google Scholar]
  • 27.Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumor promotion. Nature. 1984;308:693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  • 28.Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986;233:305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  • 29.Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988;334:661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  • 30.Ohno S., Kawasaki H., Imajoh S., Suzuki K., Inagaki M., Yokokura H., Sakoh T., Hidaka H. Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature. 1987;325:161–166. doi: 10.1038/325161a0. [DOI] [PubMed] [Google Scholar]
  • 31.Ohno K., Suzumura A., Sawada M., Marunouchi T. Production of granulocyte/macrophage colony-stimulating factor by cultured astrocytes. Biochem. Biophys. Res. Commun. 1990;169:719–724. doi: 10.1016/0006-291x(90)90390-9. [DOI] [PubMed] [Google Scholar]
  • 32.Ono Y., Kurokawa T., Fujii T., Kawahara K., Nishimura O., Igarashi K., Kikkawa U., Ogita K., Nishizuka Y. Two types of complementary DNAs of rat brain protein kinase C; heterogeneity determined by alternative splicing. FEBS Lett. 1986;206:347–352. doi: 10.1016/0014-5793(86)81010-9. [DOI] [PubMed] [Google Scholar]
  • 33.Ono Y., Kikkawa U., Ogita K., Fujii T., Kurokawa T., Asaoka K., Sekiguchi K., Ase K., Igarashi K., Nishizuka Y. Expression and properties of two types of protein kinase C determined by alternative splicing from a single gene. Science. 1987;236:1116–1120. doi: 10.1126/science.3576226. [DOI] [PubMed] [Google Scholar]
  • 34.Pardee A.B. G1 events and regulation of cell proliferation. Science. 1989;246:603–608. doi: 10.1126/science.2683075. [DOI] [PubMed] [Google Scholar]
  • 35.Pardee A.B., Dubrow R., Hamlin J.L., Kletzein R.R. Animal cell cycle. Annu. Rev. Biochem. 1978;47:715–750. doi: 10.1146/annurev.bi.47.070178.003435. [DOI] [PubMed] [Google Scholar]
  • 36.Parker P.J., Coussens L., Totty N., Rhee L., Young S., Chen E., Sabel S., Waterfield M.D., Ullrich A. The complete primary structure of protein kinase C — the major phorbol ester receptor. Science. 1986;233:853–859. doi: 10.1126/science.3755547. [DOI] [PubMed] [Google Scholar]
  • 37.Pearce B., Cambray-Deakin M., Morrow C., Grimble J., Murphy S. Activation of muscarinic and β1-adrenergic receptors on astrocytes results in the accumulation of inositol phosphate. J. Neurochem. 1985;45:1534–1540. doi: 10.1111/j.1471-4159.1985.tb07224.x. [DOI] [PubMed] [Google Scholar]
  • 38.Saito N., Kikkawa U., Nishizuka Y., Tanaka C. Distribution of protein kinase C-like immunoreactive neurons in rat brain. J. Neurosci. 1988;8:369–382. doi: 10.1523/JNEUROSCI.08-02-00369.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Sawada M., Suzumura A., Yamamoto H., Marunouchi T. Macrophage-like properties of isolated mouse microglia cells. Neurochem. Res. 1988;13:1082. [Google Scholar]
  • 40.Sawada M., Kondo N., Suzumura A., Marunouchi T. Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res. 1989;491:394–397. doi: 10.1016/0006-8993(89)90078-4. [DOI] [PubMed] [Google Scholar]
  • 41.Sawada M., Ohno K., Kondo N., Suzumura A., Marunouchi T. Immunoregulatory roles of isolated microglia and astrocytes in culture. Neurosci. Res. 1989;9:s121. doi: 10.1016/0006-8993(89)90078-4. (suppl.) [DOI] [PubMed] [Google Scholar]
  • 42.Sawada M., Suzumura A., Yamamoto H., Marunouchi T. Activation and proliferation of the isolated microglia by colony stimulating factor-1 and possible involvement of protein kinase C. Brain Res. 1990;509:119–124. doi: 10.1016/0006-8993(90)90317-5. [DOI] [PubMed] [Google Scholar]
  • 43.Sawada M., Suzumura A., Marunouchi T. TNFα induces IL-6 production by astrocytes but not by microglia. Brain Res. 1992;583:296–299. doi: 10.1016/s0006-8993(10)80037-x. [DOI] [PubMed] [Google Scholar]
  • 44.Suzumura A., Bhat S., Eccleston P.A., Lisak R.P., Silberberg D.H. The isolation and long-term culture of oligodendrocytes from newborn mouse brain. Brain Res. 1984;324:379–383. doi: 10.1016/0006-8993(84)90054-4. [DOI] [PubMed] [Google Scholar]
  • 45.Suzumura A., Lavi E., Bhat S., Murasko D., Weiss S.R., Silberberg D.H. Induction of glial cell MHC antigen expression in neurotropic coronavirus infections: Characterization of the H-2-inducing soluble factor elaborated by infected brain cells. J. Immunol. 1988;140:2068–2072. [PubMed] [Google Scholar]
  • 46.Suzumura A., Lavi E., Weiss S.R., Silberberg D. Coronavirus infection induces H-2 antigen expression on oligodendrocytes and astrocytes. Science. 1986;232:991–993. doi: 10.1126/science.3010460. [DOI] [PubMed] [Google Scholar]
  • 47.Suzumura A., Mezitis S.G.E., Gonatas N.K., Silberberg D.H. MHC antigen expression on bulk isolated macrophage-microglia from newborn mouse brain: induction of Ia antigen expression by γ-interferon. J. Neuroimmunol. 1987;15:263–278. doi: 10.1016/0165-5728(87)90121-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Tamaoki T., Nomoto H., Takahashi I., Kato Y., Morimoto M., Tomita F. Staurosporine: a potent inhibitor of phospholipid/Ca2+-dependent protein kinase. Biochem. Biophys. Res. Commun. 1986;135:397–402. doi: 10.1016/0006-291x(86)90008-2. [DOI] [PubMed] [Google Scholar]
  • 49.Wekerle H., Linington C., Lassmann H., Mayermann R. Cellular immune reactivity within the CNS. Trends Neurosci. 1986;9:271–277. [Google Scholar]

Articles from Brain Research are provided here courtesy of Elsevier

RESOURCES