Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Aug 15;89(16):7481–7485. doi: 10.1073/pnas.89.16.7481

Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C.

M Olivier 1, R W Brownsey 1, N E Reiner 1
PMCID: PMC49734  PMID: 1323839

Abstract

Stimulus-response coupling through protein kinase C (PKC) was shown to be defective in mononuclear phagocytes (M phi) infected with Leishmania donovani. Phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst activity and protein phosphorylation were markedly attenuated in infected M phi. These results were not explained either by quantitative alterations in amounts of PKC or by altered phorbol ester binding but were related to defects in kinase activation. Analysis in vitro of the kinetic properties of PKC from infected M phi revealed an approximately 2-fold increase in the concentration of 1,2-dioleoyl-rac-glycerol required to achieve half-maximal kinase activation. Evidence for abnormal PKC activation in vivo was reflected by attenuation of PMA-induced translocation of enzyme to the particulate fraction of infected cells. These results provide direct evidence that infection with Leishmania inhibits activation of, and therefore intracellular signaling dependent on, PKC. Inhibition of stimulus-response coupling through PKC provides a basis for understanding impairment of cellular activation by Leishmania and may contribute to chronic infection.

Full text

PDF
7481

Images in this article

7483Image
on p.7483
7484Image
on p.7484

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen B. G., Katz S. Isolation and characterization of the calcium- and phospholipid-dependent protein kinase (protein kinase C) subtypes from bovine heart. Biochemistry. 1991 Apr 30;30(17):4334–4343. doi: 10.1021/bi00231a032. [DOI] [PubMed] [Google Scholar]
  2. Baldwin G. C., Fleischmann J., Chung Y., Koyanagi Y., Chen I. S., Golde D. W. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc Natl Acad Sci U S A. 1990 May;87(10):3933–3937. doi: 10.1073/pnas.87.10.3933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bliska J. B., Guan K. L., Dixon J. E., Falkow S. Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1187–1191. doi: 10.1073/pnas.88.4.1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bogdan C., Stenger S., Röllinghoff M., Solbach W. Cytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon-gamma to activate murine macrophages for killing of Leishmania major amastigotes. Eur J Immunol. 1991 Feb;21(2):327–333. doi: 10.1002/eji.1830210213. [DOI] [PubMed] [Google Scholar]
  5. Borner C., Filipuzzi I., Wartmann M., Eppenberger U., Fabbro D. Biosynthesis and posttranslational modifications of protein kinase C in human breast cancer cells. J Biol Chem. 1989 Aug 15;264(23):13902–13909. [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Brownsey R. W., Dong G. W., Lam V., McGreer W. Studies on protein phosphorylation using subcellular fractions from insulin-treated white adipose tissue of rats. Biochem Cell Biol. 1988 Apr;66(4):296–308. doi: 10.1139/o88-039. [DOI] [PubMed] [Google Scholar]
  8. Brownsey R. W., Hughes W. A., Denton R. M. Adrenaline and the regulation of acetyl-coenzyme A carboxylase in rat epididymal adipose tissue. Inactivation of the enzyme is associated with phosphorylation and can be reversed on dephosphorylation. Biochem J. 1979 Oct 15;184(1):23–32. doi: 10.1042/bj1840023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buchmüller-Rouiller Y., Mauël J. Impairment of the oxidative metabolism of mouse peritoneal macrophages by intracellular Leishmania spp. Infect Immun. 1987 Mar;55(3):587–593. doi: 10.1128/iai.55.3.587-593.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Das S., Saha A. K., Remaley A. T., Glew R. H., Dowling J. N., Kajiyoshi M., Gottlieb M. Hydrolysis of phosphoproteins and inositol phosphates by cell surface phosphatase of Leishmania donovani. Mol Biochem Parasitol. 1986 Aug;20(2):143–153. doi: 10.1016/0166-6851(86)90026-5. [DOI] [PubMed] [Google Scholar]
  11. Denton R. M., McCormack J. G. Ca2+ transport by mammalian mitochondria and its role in hormone action. Am J Physiol. 1985 Dec;249(6 Pt 1):E543–E554. doi: 10.1152/ajpendo.1985.249.6.E543. [DOI] [PubMed] [Google Scholar]
  12. Descoteaux A., Matlashewski G. c-fos and tumor necrosis factor gene expression in Leishmania donovani-infected macrophages. Mol Cell Biol. 1989 Nov;9(11):5223–5227. doi: 10.1128/mcb.9.11.5223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Descoteaux A., Turco S. J., Sacks D. L., Matlashewski G. Leishmania donovani lipophosphoglycan selectively inhibits signal transduction in macrophages. J Immunol. 1991 Apr 15;146(8):2747–2753. [PubMed] [Google Scholar]
  14. Fan X. D., Goldberg M., Bloom B. R. Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5122–5125. doi: 10.1073/pnas.85.14.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Green S. J., Crawford R. M., Hockmeyer J. T., Meltzer M. S., Nacy C. A. Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha. J Immunol. 1990 Dec 15;145(12):4290–4297. [PubMed] [Google Scholar]
  16. Hannun Y. A., Loomis C. R., Bell R. M. Activation of protein kinase C by Triton X-100 mixed micelles containing diacylglycerol and phosphatidylserine. J Biol Chem. 1985 Aug 25;260(18):10039–10043. [PubMed] [Google Scholar]
  17. Jardim A., Tolson D. L., Turco S. J., Pearson T. W., Olafson R. W. The Leishmania donovani lipophosphoglycan T lymphocyte-reactive component is a tightly associated protein complex. J Immunol. 1991 Nov 15;147(10):3538–3544. [PubMed] [Google Scholar]
  18. Kiyotaki C., Bloom B. R. Activation of murine macrophage cell lines. Possible involvement of protein kinases in stimulation of superoxide production. J Immunol. 1984 Aug;133(2):923–931. [PubMed] [Google Scholar]
  19. Klee C. B., Crouch T. H., Krinks M. H. Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6270–6273. doi: 10.1073/pnas.76.12.6270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  21. Liew F. Y. Regulation of cell-mediated immunity in leishmaniasis. Curr Top Microbiol Immunol. 1990;155:53–64. doi: 10.1007/978-3-642-74983-4_4. [DOI] [PubMed] [Google Scholar]
  22. Liles W. C., Hunter D. D., Meier K. E., Nathanson N. M. Activation of protein kinase C induces rapid internalization and subsequent degradation of muscarinic acetylcholine receptors in neuroblastoma cells. J Biol Chem. 1986 Apr 25;261(12):5307–5313. [PubMed] [Google Scholar]
  23. Makowske M., Ballester R., Cayre Y., Rosen O. M. Immunochemical evidence that three protein kinase C isozymes increase in abundance during HL-60 differentiation induced by dimethyl sulfoxide and retinoic acid. J Biol Chem. 1988 Mar 5;263(7):3402–3410. [PubMed] [Google Scholar]
  24. McConville M. J., Blackwell J. M. Developmental changes in the glycosylated phosphatidylinositols of Leishmania donovani. Characterization of the promastigote and amastigote glycolipids. J Biol Chem. 1991 Aug 15;266(23):15170–15179. [PubMed] [Google Scholar]
  25. McNeely T. B., Rosen G., Londner M. V., Turco S. J. Inhibitory effects on protein kinase C activity by lipophosphoglycan fragments and glycosylphosphatidylinositol antigens of the protozoan parasite Leishmania. Biochem J. 1989 Apr 15;259(2):601–604. doi: 10.1042/bj2590601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moyes C. D., Buck L. T., Hochachka P. W. Mitochondrial and peroxisomal fatty acid oxidation in elasmobranchs. Am J Physiol. 1990 Mar;258(3 Pt 2):R756–R762. doi: 10.1152/ajpregu.1990.258.3.R756. [DOI] [PubMed] [Google Scholar]
  27. Myers M. A., McPhail L. C., Snyderman R. Redistribution of protein kinase C activity in human monocytes: correlation with activation of the respiratory burst. J Immunol. 1985 Nov;135(5):3411–3416. [PubMed] [Google Scholar]
  28. O'Farrell P. H. High resolution two-dimensional electrophoresis of proteins. J Biol Chem. 1975 May 25;250(10):4007–4021. [PMC free article] [PubMed] [Google Scholar]
  29. Olivier M., Baimbridge K. G., Reiner N. E. Stimulus-response coupling in monocytes infected with Leishmania. Attenuation of calcium transients is related to defective agonist-induced accumulation of inositol phosphates. J Immunol. 1992 Feb 15;148(4):1188–1196. [PubMed] [Google Scholar]
  30. Perrella F. W., Hellmig B. D., Diamond L. Up regulation of the phorbol ester receptor-protein kinase C in HL-60 variant cells. Cancer Res. 1986 Feb;46(2):567–572. [PubMed] [Google Scholar]
  31. Pick E. Microassays for superoxide and hydrogen peroxide production and nitroblue tetrazolium reduction using an enzyme immunoassay microplate reader. Methods Enzymol. 1986;132:407–421. doi: 10.1016/s0076-6879(86)32026-3. [DOI] [PubMed] [Google Scholar]
  32. Pinching A. J., Nye K. E. Defective signal transduction--a common pathway for cellular dysfunction in HIV infection? Immunol Today. 1990 Jul;11(7):256–259. doi: 10.1016/0167-5699(90)90100-n. [DOI] [PubMed] [Google Scholar]
  33. Reiner N. E., Ng W., Ma T., McMaster W. R. Kinetics of gamma interferon binding and induction of major histocompatibility complex class II mRNA in Leishmania-infected macrophages. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4330–4334. doi: 10.1073/pnas.85.12.4330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reiner N. E., Ng W., Wilson C. B., McMaster W. R., Burchett S. K. Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1. J Clin Invest. 1990 Jun;85(6):1914–1924. doi: 10.1172/JCI114654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schütze S., Nottrott S., Pfizenmaier K., Krönke M. Tumor necrosis factor signal transduction. Cell-type-specific activation and translocation of protein kinase C. J Immunol. 1990 Apr 1;144(7):2604–2608. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES