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
. 1991 Jul 15;88(14):6229–6233. doi: 10.1073/pnas.88.14.6229

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

T Hultsch 1, M W Albers 1, S L Schreiber 1, R J Hohman 1
PMCID: PMC52056  PMID: 1712484

Abstract

Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism.

Full text

PDF
6231

Images in this article

6231Image
on p.6231
6231Image
on p.6231
6231Image
on p.6231
6232Image
on p.6232
6233Image
on p.6233

Selected References

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

  1. Barsumian E. L., Isersky C., Petrino M. G., Siraganian R. P. IgE-induced histamine release from rat basophilic leukemia cell lines: isolation of releasing and nonreleasing clones. Eur J Immunol. 1981 Apr;11(4):317–323. doi: 10.1002/eji.1830110410. [DOI] [PubMed] [Google Scholar]
  2. Beaven M. A., Cunha-Melo J. R. Membrane phosphoinositide-activated signals in mast cells and basophils. Prog Allergy. 1988;42:123–184. [PubMed] [Google Scholar]
  3. Bierer B. E., Mattila P. S., Standaert R. F., Herzenberg L. A., Burakoff S. J., Crabtree G., Schreiber S. L. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9231–9235. doi: 10.1073/pnas.87.23.9231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bierer B. E., Somers P. K., Wandless T. J., Burakoff S. J., Schreiber S. L. Probing immunosuppressant action with a nonnatural immunophilin ligand. Science. 1990 Oct 26;250(4980):556–559. doi: 10.1126/science.1700475. [DOI] [PubMed] [Google Scholar]
  5. Burd P. R., Rogers H. W., Gordon J. R., Martin C. A., Jayaraman S., Wilson S. D., Dvorak A. M., Galli S. J., Dorf M. E. Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med. 1989 Jul 1;170(1):245–257. doi: 10.1084/jem.170.1.245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Collado-Escobar D., Cunha-Melo J. R., Beaven M. A. Treatment with dexamethasone down-regulates IgE-receptor-mediated signals and up-regulates adenosine-receptor-mediated signals in a rat mast cell (RBL-2H3) line. J Immunol. 1990 Jan 1;144(1):244–250. [PubMed] [Google Scholar]
  7. Dumont F. J., Melino M. R., Staruch M. J., Koprak S. L., Fischer P. A., Sigal N. H. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol. 1990 Feb 15;144(4):1418–1424. [PubMed] [Google Scholar]
  8. Dumont F. J., Staruch M. J., Koprak S. L., Melino M. R., Sigal N. H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol. 1990 Jan 1;144(1):251–258. [PubMed] [Google Scholar]
  9. Elliott J. F., Lin Y., Mizel S. B., Bleackley R. C., Harnish D. G., Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984 Dec 21;226(4681):1439–1441. doi: 10.1126/science.6334364. [DOI] [PubMed] [Google Scholar]
  10. Emmel E. A., Verweij C. L., Durand D. B., Higgins K. M., Lacy E., Crabtree G. R. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science. 1989 Dec 22;246(4937):1617–1620. doi: 10.1126/science.2595372. [DOI] [PubMed] [Google Scholar]
  11. Foxwell B. M., Hiestand P. C., Wenger R., Ryffel B. A comparison of cyclosporine binding by cyclophilin and calmodulin and the identification of a novel 45 KD cyclosporine-binding phosphoprotein in Jurkat cells. Transplantation. 1988 Aug;46(2 Suppl):35S–40S. doi: 10.1097/00007890-198808001-00007. [DOI] [PubMed] [Google Scholar]
  12. Granelli-Piperno A., Nolan P., Inaba K., Steinman R. M. The effect of immunosuppressive agents on the induction of nuclear factors that bind to sites on the interleukin 2 promoter. J Exp Med. 1990 Dec 1;172(6):1869–1872. doi: 10.1084/jem.172.6.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Harding M. W., Galat A., Uehling D. E., Schreiber S. L. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature. 1989 Oct 26;341(6244):758–760. doi: 10.1038/341758a0. [DOI] [PubMed] [Google Scholar]
  14. Hohman R. J., Hultsch T. Cyclosporin A: new insights for cell biologists and biochemists. New Biol. 1990 Aug;2(8):663–672. [PubMed] [Google Scholar]
  15. Hunt T. Cytoplasmic anchoring proteins and the control of nuclear localization. Cell. 1989 Dec 22;59(6):949–951. doi: 10.1016/0092-8674(89)90747-2. [DOI] [PubMed] [Google Scholar]
  16. Kinet J. P. Antibody-cell interactions: Fc receptors. Cell. 1989 May 5;57(3):351–354. doi: 10.1016/0092-8674(89)90910-0. [DOI] [PubMed] [Google Scholar]
  17. Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maeyama K., Hohman R. J., Ali H., Cunha-Melo J. R., Beaven M. A. Assessment of IgE-receptor function through measurement of hydrolysis of membrane inositol phospholipids. New insights on the phenomena of biphasic antigen concentration-response curves and desensitization. J Immunol. 1988 Jun 1;140(11):3919–3927. [PubMed] [Google Scholar]
  19. Maeyama K., Hohman R. J., Metzger H., Beaven M. A. Quantitative relationships between aggregation of IgE receptors, generation of intracellular signals, and histamine secretion in rat basophilic leukemia (2H3) cells. Enhanced responses with heavy water. J Biol Chem. 1986 Feb 25;261(6):2583–2592. [PubMed] [Google Scholar]
  20. Metzger H., Alcaraz G., Hohman R., Kinet J. P., Pribluda V., Quarto R. The receptor with high affinity for immunoglobulin E. Annu Rev Immunol. 1986;4:419–470. doi: 10.1146/annurev.iy.04.040186.002223. [DOI] [PubMed] [Google Scholar]
  21. Oliver J. M., Seagrave J., Stump R. F., Pfeiffer J. R., Deanin G. G. Signal transduction and cellular response in RBL-2H3 mast cells. Prog Allergy. 1988;42:185–245. [PubMed] [Google Scholar]
  22. Plaut M., Pierce J. H., Watson C. J., Hanley-Hyde J., Nordan R. P., Paul W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores. Nature. 1989 May 4;339(6219):64–67. doi: 10.1038/339064a0. [DOI] [PubMed] [Google Scholar]
  23. Schreiber S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991 Jan 18;251(4991):283–287. doi: 10.1126/science.1702904. [DOI] [PubMed] [Google Scholar]
  24. Siekierka J. J., Hung S. H., Poe M., Lin C. S., Sigal N. H. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature. 1989 Oct 26;341(6244):755–757. doi: 10.1038/341755a0. [DOI] [PubMed] [Google Scholar]
  25. Starzl T. E., Todo S., Fung J., Demetris A. J., Venkataramman R., Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989 Oct 28;2(8670):1000–1004. doi: 10.1016/s0140-6736(89)91014-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Trenn G., Taffs R., Hohman R., Kincaid R., Shevach E. M., Sitkovsky M. Biochemical characterization of the inhibitory effect of CsA on cytolytic T lymphocyte effector functions. J Immunol. 1989 Jun 1;142(11):3796–3802. [PubMed] [Google Scholar]
  27. Varshavsky A. Naming a targeting signal. Cell. 1991 Jan 11;64(1):13–15. doi: 10.1016/0092-8674(91)90202-a. [DOI] [PubMed] [Google Scholar]
  28. Wicker L. S., Boltz R. C., Jr, Matt V., Nichols E. A., Peterson L. B., Sigal N. H. Suppression of B cell activation by cyclosporin A, FK506 and rapamycin. Eur J Immunol. 1990 Oct;20(10):2277–2283. doi: 10.1002/eji.1830201017. [DOI] [PubMed] [Google Scholar]
  29. Wodnar-Filipowicz A., Heusser C. H., Moroni C. Production of the haemopoietic growth factors GM-CSF and interleukin-3 by mast cells in response to IgE receptor-mediated activation. Nature. 1989 May 11;339(6220):150–152. doi: 10.1038/339150a0. [DOI] [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