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
. 1984 Feb;81(3):862–866. doi: 10.1073/pnas.81.3.862

Intracellular lymphocyte activation and carrier-mediated transport of C8-substituted guanine ribonucleosides.

M G Goodman, W O Weigle
PMCID: PMC344938  PMID: 6583684

Abstract

The studies described in this report constitute evidence substantiating that certain exogenous nucleoside derivatives can activate lymphocytes by acting intracellularly. These molecules, the C8-substituted guanine ribonucleosides, have recently been demonstrated to exert potent immunostimulatory and immunoregulatory activities both in vitro and in vivo. The current studies were undertaken to investigate whether the site of induction of mitogenesis in murine B lymphocytes by these compounds was intracellular or at the plasma membrane. Uptake of 8-bromoguanosine was found to proceed by carrier-mediated transport. Like that described for adenosine, the uptake system for 8-bromoguanosine could be resolved into high-affinity and low-affinity components. The hypothesis that the C8-substituted guanine ribonucleosides act intracellularly was tested in several ways. Immobilization of these substituted nucleosides, either on Sepharose beads or in the form of high molecular weight polymers, resulted in total loss of their mitogenicity. In addition, maneuvers designed to diminish plasma membrane fluidity interfered with transmembrane signaling by surface membrane-directed mitogens far more than they did with activation by the substituted nucleosides. Furthermore, modulation of surface membrane protein (IgM) with anti-IgM antibodies similarly resulted in differential inhibition of transmembrane signals with relatively little effect on activation by 8-mercaptoguanosine. Taken together, these data are consistent with the hypothesis that the C8-substituted guanine ribonucleosides trigger the cell at an intracellular site.

Full text

PDF
862

Selected References

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

  1. Chantot J. -F., Guschlbauer W. Physicochemical properties of nucleosides 3. Gel formation by 8-bromoguanosine. FEBS Lett. 1969 Aug;4(3):173–176. doi: 10.1016/0014-5793(69)80227-9. [DOI] [PubMed] [Google Scholar]
  2. Friend P. S., Theofilopoulos A. N., Fidler J. M., Dixon F. J. B-cell suppression by anti-IgM antibody: humoral and cellular analyses. Cell Immunol. 1981 Jul 1;61(2):404–415. doi: 10.1016/0008-8749(81)90388-9. [DOI] [PubMed] [Google Scholar]
  3. Goodman M. G., Fidler J. M., Weigle W. O. Nonspecific activation of murine lymphocytes. IV. Proliferation of a distinct, late maturing lymphocyte subpopulation induced by 2-mercaptoethanol. J Immunol. 1978 Nov;121(5):1905–1913. [PubMed] [Google Scholar]
  4. Goodman M. G., Weigle W. O. Activation of lymphocytes by a thiol-derivatized nucleoside: characterization of cellular parameters and responsive subpopulations. J Immunol. 1983 Feb;130(2):551–557. [PubMed] [Google Scholar]
  5. Goodman M. G., Weigle W. O. Activation of lymphocytes by brominated nucleoside and cyclic nucleotide analogues: implications for the "second messenger" function of cyclic GMP. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7604–7608. doi: 10.1073/pnas.78.12.7604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goodman M. G., Weigle W. O. Bromination of guanosine and cyclic GMP confers resistance to metabolic processing by B cells. J Immunol. 1982 Dec;129(6):2715–2717. [PubMed] [Google Scholar]
  7. Goodman M. G., Weigle W. O. Derivatized guanine nucleosides: a new class of adjuvant for in vitro antibody responses. J Immunol. 1983 Jun;130(6):2580–2585. [PubMed] [Google Scholar]
  8. Goodman M. G., Weigle W. O. Induction of immunoglobulin secretion by a simple nucleoside derivative. J Immunol. 1982 Jun;128(6):2399–2404. [PubMed] [Google Scholar]
  9. Goodman M. G., Weigle W. O. Manifold amplification of in vivo immunity in normal and immunodeficient mice by ribonucleosides derivatized at C8 of guanine. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3452–3455. doi: 10.1073/pnas.80.11.3452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goodman M. G., Weigle W. O. T cell-replacing activity of C8-derivatized guanine ribonucleosides. J Immunol. 1983 May;130(5):2042–2045. [PubMed] [Google Scholar]
  11. Gregory S. H., Kern M. Mitogenic response of T-cell subclasses to agarose-linked and to free ribonucleotides. Immunology. 1981 Mar;42(3):451–457. [PMC free article] [PubMed] [Google Scholar]
  12. Kearney J. F., Klein J., Bockman D. E., Cooper M. D., Lawton A. R. B cell differentiation induced by lipopolysaccharide. V. Suppression of plasma cell maturation by anti-mu: mode of action and characteristics of suppressed cells. J Immunol. 1978 Jan;120(1):158–166. [PubMed] [Google Scholar]
  13. Lafer E. M., Möller A., Nordheim A., Stollar B. D., Rich A. Antibodies specific for left-handed Z-DNA. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3546–3550. doi: 10.1073/pnas.78.6.3546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Londos C., Cooper D. M., Wolff J. Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A. 1980 May;77(5):2551–2554. doi: 10.1073/pnas.77.5.2551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marone G., Findlay S. R., Lichtenstein L. M. Adenosine receptor on human basophils: modulation of histamine release. J Immunol. 1979 Oct;123(4):1473–1477. [PubMed] [Google Scholar]
  16. Mishell R. I., Dutton R. W. Immunization of dissociated spleen cell cultures from normal mice. J Exp Med. 1967 Sep 1;126(3):423–442. doi: 10.1084/jem.126.3.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rivnay B., Globerson A., Shinitzky M. Peturbation of lymphocyte response to concanavalin A by exogenous cholesterol and lecithin. Eur J Immunol. 1978 Mar;8(3):185–189. doi: 10.1002/eji.1830080309. [DOI] [PubMed] [Google Scholar]
  18. Schrader J. W. Antagonism of B lymphocyte mitogenesis by anti-immunoglobulin antibody. J Immunol. 1975 Aug;115(2):323–326. [PubMed] [Google Scholar]
  19. Sidman C. L., Unanue E. R. Control of proliferation and differentiation in B lymphocytes by anti-Ig antibodies and a serum-derived cofactor. Proc Natl Acad Sci U S A. 1978 May;75(5):2401–2405. doi: 10.1073/pnas.75.5.2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Strauss P. R., Sheehan J. M., Kashket E. R. Membrane transport by murine lymphocytes. I. A rapid sampling technique as applied to the adenosine and thymidine systems. J Exp Med. 1976 Oct 1;144(4):1009–1021. doi: 10.1084/jem.144.4.1009. [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