Skip to main content
PMC 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
. 1990 Dec;87(23):9421–9425. doi: 10.1073/pnas.87.23.9421

Regulation of interleukin 2-dependent growth responses by glycosylphosphatidylinositol molecules.

I Merida 1, J C Pratt 1, G N Gaulton 1
PMCID: PMC55177  PMID: 2147515

Abstract

The molecular mechanism of signal transduction through the interleukin 2 (IL-2) receptor remains an enigma. Glycosylphosphatidylinositol (GPI) lipids were investigated as one component of this process. IL-2 stimulated the rapid (30 sec) loss of greater than 50% of GPI in the IL-2-dependent T-cell line CTLL-2. Half-maximal GPI loss was detected at 40 pM IL-2, coincident with the EC50 (20 pM) for IL-2-induced proliferation of this cell line. This effect was specifically inhibited by antibodies that bind either IL-2 or the IL-2 receptor. The loss of GPI was mirrored by the accumulation of both polar inositolphosphoglycan (IPG) and diacylglycerol lipid fragments within cells. Increases in lipids were initially restricted to myristoyl diacylglycerol but were followed by the accumulation of myristoyl phosphatidic acid. These results are indicative of IL-2-dependent hydrolysis of GPI in T cells. The biological relevance of this hydrolysis was demonstrated by synergism of purified IPG with IL-2 in T-cell proliferation responses. The inclusion of IPG (0.1 microM) in determinations of IL-2-dependent CTLL-2 growth shifted the EC50 from 20 to 7 pM IL-2. IPG had no effect on either the number or affinity of IL-2 receptors; therefore, half-maximal CTLL-2 proliferation was obtained at less than 10% IL-2 receptor occupancy. These results demonstrate that GPI lipids are an important component of the biological response to IL-2.

Full text

PDF
9421

Selected References

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

  1. Alemany S., Mato J. M., Strålfors P. Phospho-dephospho-control by insulin is mimicked by a phospho-oligosaccharide in adipocytes. Nature. 1987 Nov 5;330(6143):77–79. doi: 10.1038/330077a0. [DOI] [PubMed] [Google Scholar]
  2. Bocckino S. B., Blackmore P. F., Wilson P. B., Exton J. H. Phosphatidate accumulation in hormone-treated hepatocytes via a phospholipase D mechanism. J Biol Chem. 1987 Nov 5;262(31):15309–15315. [PubMed] [Google Scholar]
  3. Cantrell D. A., Smith K. A. The interleukin-2 T-cell system: a new cell growth model. Science. 1984 Jun 22;224(4655):1312–1316. doi: 10.1126/science.6427923. [DOI] [PubMed] [Google Scholar]
  4. Cantrell D. A., Smith K. A. Transient expression of interleukin 2 receptors. Consequences for T cell growth. J Exp Med. 1983 Dec 1;158(6):1895–1911. doi: 10.1084/jem.158.6.1895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chan B. L., Chao M. V., Saltiel A. R. Nerve growth factor stimulates the hydrolysis of glycosylphosphatidylinositol in PC-12 cells: a mechanism of protein kinase C regulation. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1756–1760. doi: 10.1073/pnas.86.6.1756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Conzelmann A., Spiazzi A., Bron C. Glycolipid anchors are attached to Thy-1 glycoprotein rapidly after translation. Biochem J. 1987 Sep 15;246(3):605–610. doi: 10.1042/bj2460605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Farrar W. L., Cleveland J. L., Beckner S. K., Bonvini E., Evans S. W. Biochemical and molecular events associated with interleukin 2 regulation of lymphocyte proliferation. Immunol Rev. 1986 Aug;92:49–65. doi: 10.1111/j.1600-065x.1986.tb01493.x. [DOI] [PubMed] [Google Scholar]
  8. Gaulton G. N., Bangs J., Maddock S., Springer T., Eardley D. D., Strom T. B. Characterization of a monoclonal rat anti-mouse interleukin 2 (IL-2) receptor antibody and its use in the biochemical characterization of the murine IL-2 receptor. Clin Immunol Immunopathol. 1985 Jul;36(1):18–29. doi: 10.1016/0090-1229(85)90035-2. [DOI] [PubMed] [Google Scholar]
  9. Gaulton G. N., Kelly K. L., Pawlowski J., Mato J. M., Jarett L. Regulation and function of an insulin-sensitive glycosyl-phosphatidylinositol during T lymphocyte activation. Cell. 1988 Jun 17;53(6):963–970. doi: 10.1016/s0092-8674(88)90509-0. [DOI] [PubMed] [Google Scholar]
  10. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  11. Gillis S., Watson J. Interleukin-2 induction of hapten-specific cytolytic T cells in nude mice. J Immunol. 1981 Apr;126(4):1245–1248. [PubMed] [Google Scholar]
  12. Howe R. C., Milstone D. S., Ratliff T. L., Russell J. H. Interleukin 2-mediated induction of lytic activity in a cloned murine CTL line. J Immunol. 1985 Apr;134(4):2414–2418. [PubMed] [Google Scholar]
  13. Kelly K. L., Mato J. M., Merida I., Jarett L. Glucose transport and antilipolysis are differentially regulated by the polar head group of an insulin-sensitive glycophospholipid. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6404–6407. doi: 10.1073/pnas.84.18.6404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kelly K. L., Merida I., Wong E. H., DiCenzo D., Mato J. M. A phospho-oligosaccharide mimics the effect of insulin to inhibit isoproterenol-dependent phosphorylation of phospholipid methyltransferase in isolated adipocytes. J Biol Chem. 1987 Nov 5;262(31):15285–15290. [PubMed] [Google Scholar]
  15. Krakow J. L., Hereld D., Bangs J. D., Hart G. W., Englund P. T. Identification of a glycolipid precursor of the Trypanosoma brucei variant surface glycoprotein. J Biol Chem. 1986 Sep 15;261(26):12147–12153. [PubMed] [Google Scholar]
  16. Leonard W. J., Depper J. M., Uchiyama T., Smith K. A., Waldmann T. A., Greene W. C. A monoclonal antibody that appears to recognize the receptor for human T-cell growth factor; partial characterization of the receptor. Nature. 1982 Nov 18;300(5889):267–269. doi: 10.1038/300267a0. [DOI] [PubMed] [Google Scholar]
  17. Low M. G., Saltiel A. R. Structural and functional roles of glycosyl-phosphatidylinositol in membranes. Science. 1988 Jan 15;239(4837):268–275. doi: 10.1126/science.3276003. [DOI] [PubMed] [Google Scholar]
  18. Maddock E. O., Maddock S. W., Kelley V. E., Strom T. B. Rapid stereospecific stimulation of lymphocytic metabolism by interleukin 2. J Immunol. 1985 Dec;135(6):4004–4008. [PubMed] [Google Scholar]
  19. Mato J. M., Kelly K. L., Abler A., Jarett L., Corkey B. E., Cashel J. A., Zopf D. Partial structure of an insulin-sensitive glycophospholipid. Biochem Biophys Res Commun. 1987 Jul 31;146(2):764–770. doi: 10.1016/0006-291x(87)90595-x. [DOI] [PubMed] [Google Scholar]
  20. Mato J. M., Kelly K. L., Abler A., Jarett L. Identification of a novel insulin-sensitive glycophospholipid from H35 hepatoma cells. J Biol Chem. 1987 Feb 15;262(5):2131–2137. [PubMed] [Google Scholar]
  21. Merida I., Gaulton G. N. Protein tyrosine phosphorylation associated with activation of the interleukin 2 receptor. J Biol Chem. 1990 Apr 5;265(10):5690–5694. [PubMed] [Google Scholar]
  22. Mills G. B., Cheung R. K., Grinstein S., Gelfand E. W. Interleukin 2-induced lymphocyte proliferation is independent of increases in cytosolic-free calcium concentrations. J Immunol. 1985 Apr;134(4):2431–2435. [PubMed] [Google Scholar]
  23. Mills G. B., Girard P., Grinstein S., Gelfand E. W. Interleukin-2 induces proliferation of T lymphocyte mutants lacking protein kinase C. Cell. 1988 Oct 7;55(1):91–100. doi: 10.1016/0092-8674(88)90012-8. [DOI] [PubMed] [Google Scholar]
  24. Mills G. B., Stewart D. J., Mellors A., Gelfand E. W. Interleukin 2 does not induce phosphatidylinositol hydrolysis in activated T cells. J Immunol. 1986 Apr 15;136(8):3019–3024. [PubMed] [Google Scholar]
  25. Robb R. J., Munck A., Smith K. A. T cell growth factor receptors. Quantitation, specificity, and biological relevance. J Exp Med. 1981 Nov 1;154(5):1455–1474. doi: 10.1084/jem.154.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rosoff P. M., Savage N., Dinarello C. A. Interleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism. Cell. 1988 Jul 1;54(1):73–81. doi: 10.1016/0092-8674(88)90181-x. [DOI] [PubMed] [Google Scholar]
  27. Sabe H., Kondo S., Shimizu A., Tagaya Y., Yodoi J., Kobayashi N., Hatanaka M., Matsunami N., Maeda M., Noma T. Properties of human interleukin-2 receptors expressed on non-lymphoid cells by cDNA transfection. Mol Biol Med. 1984 Dec;2(6):379–396. [PubMed] [Google Scholar]
  28. Saltiel A. R., Fox J. A., Sherline P., Cuatrecasas P. Insulin-stimulated hydrolysis of a novel glycolipid generates modulators of cAMP phosphodiesterase. Science. 1986 Aug 29;233(4767):967–972. doi: 10.1126/science.3016898. [DOI] [PubMed] [Google Scholar]
  29. Saltiel A. R. Insulin generates an enzyme modulator from hepatic plasma membranes: regulation of adenosine 3',5'-monophosphate phosphodiesterase, pyruvate dehydrogenase, and adenylate cyclase. Endocrinology. 1987 Mar;120(3):967–972. doi: 10.1210/endo-120-3-967. [DOI] [PubMed] [Google Scholar]
  30. Saltiel A. R., Sherline P., Fox J. A. Insulin-stimulated diacylglycerol production results from the hydrolysis of a novel phosphatidylinositol glycan. J Biol Chem. 1987 Jan 25;262(3):1116–1121. [PubMed] [Google Scholar]
  31. Saltiel A. R., Sorbara-Cazan L. R. Inositol glycan mimics the action of insulin on glucose utilization in rat adipocytes. Biochem Biophys Res Commun. 1987 Dec 31;149(3):1084–1092. doi: 10.1016/0006-291x(87)90519-5. [DOI] [PubMed] [Google Scholar]
  32. Sharon M., Klausner R. D., Cullen B. R., Chizzonite R., Leonard W. J. Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions. Science. 1986 Nov 14;234(4778):859–863. doi: 10.1126/science.3095922. [DOI] [PubMed] [Google Scholar]
  33. Smith K. A., Favata M. F., Oroszlan S. Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol. 1983 Oct;131(4):1808–1815. [PubMed] [Google Scholar]
  34. Teshigawara K., Wang H. M., Kato K., Smith K. A. Interleukin 2 high-affinity receptor expression requires two distinct binding proteins. J Exp Med. 1987 Jan 1;165(1):223–238. doi: 10.1084/jem.165.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tigges M. A., Casey L. S., Koshland M. E. Mechanism of interleukin-2 signaling: mediation of different outcomes by a single receptor and transduction pathway. Science. 1989 Feb 10;243(4892):781–786. doi: 10.1126/science.2492678. [DOI] [PubMed] [Google Scholar]
  36. Valge V. E., Wong J. G., Datlof B. M., Sinskey A. J., Rao A. Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells. Cell. 1988 Oct 7;55(1):101–112. doi: 10.1016/0092-8674(88)90013-x. [DOI] [PubMed] [Google Scholar]
  37. Villalba M., Kelly K. L., Mato J. M. Inhibition of cyclic AMP-dependent protein kinase by the polar head group of an insulin-sensitive glycophospholipid. Biochim Biophys Acta. 1988 Jan 18;968(1):69–76. doi: 10.1016/0167-4889(88)90045-6. [DOI] [PubMed] [Google Scholar]
  38. Wang H. M., Smith K. A. The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med. 1987 Oct 1;166(4):1055–1069. doi: 10.1084/jem.166.4.1055. [DOI] [PMC free article] [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