Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Feb 1;171(2):533–544. doi: 10.1084/jem.171.2.533

Lymphokine gene expression in vivo is inhibited by cyclosporin A

PMCID: PMC2187715  PMID: 2303784

Abstract

Murine T cells were stimulated in vivo by administering allogeneic cells or mitogens into the foot pads and then examining the draining popliteal lymph nodes. Allogeneic spleen cells induced the expression of IL2 and IFN-gamma mRNAs in a time- and dose-dependent manner. Induction of these transcripts also was detected after administration of Con A and anti-CD3 mAb. An increase in DNA-synthesizing cells was observed by 48 h, and these were shown to be T cells because of their sensitivity to anti-Thy-1 but not anti-B220 mAb and complement, and because of their localization to the T-dependent areas of the lymph node. The in vivo administration of cyclosporin A (CSA) reduced several of these T cell responses. The level of DNA synthesis and the frequency of cells synthesizing DNA were decreased by approximately 75%, while the induction of IL-2 responsiveness was not substantially diminished. IL-2 and IFN-gamma transcripts were inhibited at least 70-90%, as determined by Northern blot and in situ hybridization. Although the inhibition by CSA was not as complete in animals as observed previously in tissue culture, our findings indicate that in both systems, a major site of action of CSA is to inhibit T cell growth by inhibiting lymphokine production.

Full Text

The Full Text of this article is available as a PDF (904.7 KB).

Selected References

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

  1. Andrus L., Lafferty K. J. Inhibition of T-cell activity by cyclosporin A. Scand J Immunol. 1981 May;15(5):449–458. doi: 10.1111/j.1365-3083.1982.tb00670.x. [DOI] [PubMed] [Google Scholar]
  2. Borel J. F., Feurer C., Gubler H. U., Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976 Jul;6(4):468–475. doi: 10.1007/BF01973261. [DOI] [PubMed] [Google Scholar]
  3. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  4. Chisholm P. M., Drayson M. T., Cox J. H., Ford W. L. The effects of cyclosporin on lymphocyte activation in a systemic graft-vs.-host reaction. Eur J Immunol. 1985 Oct;15(10):1054–1059. doi: 10.1002/eji.1830151018. [DOI] [PubMed] [Google Scholar]
  5. Crabtree G. R. Contingent genetic regulatory events in T lymphocyte activation. Science. 1989 Jan 20;243(4889):355–361. doi: 10.1126/science.2783497. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Gauchat J. F., Khandjian E. W., Weil R. Cyclosporin A prevents induction of the interleukin 2 receptor gene in cultured murine thymocytes. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6430–6434. doi: 10.1073/pnas.83.17.6430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Glisin V., Crkvenjakov R., Byus C. Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry. 1974 Jun 4;13(12):2633–2637. doi: 10.1021/bi00709a025. [DOI] [PubMed] [Google Scholar]
  9. Granelli-Piperno A., Andrus L., Reich E. Antibodies to interleukin 2. Effects on immune responses in vitro and in vivo. J Exp Med. 1984 Sep 1;160(3):738–750. doi: 10.1084/jem.160.3.738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Granelli-Piperno A., Andrus L., Steinman R. M. Lymphokine and nonlymphokine mRNA levels in stimulated human T cells. Kinetics, mitogen requirements, and effects of cyclosporin A. J Exp Med. 1986 Apr 1;163(4):922–937. doi: 10.1084/jem.163.4.922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Granelli-Piperno A. In situ hybridization for interleukin 2 and interleukin 2 receptor mRNA in T cells activated in the presence or absence of cyclosporin A. J Exp Med. 1988 Nov 1;168(5):1649–1658. doi: 10.1084/jem.168.5.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Granelli-Piperno A., Inaba K., Steinman R. M. Stimulation of lymphokine release from T lymphoblasts. Requirement for mRNA synthesis and inhibition by cyclosporin A. J Exp Med. 1984 Dec 1;160(6):1792–1802. doi: 10.1084/jem.160.6.1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Granelli-Piperno A., Keane M. Effects of cyclosporine A on T lymphocytes and accessory cells from human blood. Transplant Proc. 1988 Apr;20(2 Suppl 2):136–142. [PubMed] [Google Scholar]
  14. Granelli-Piperno A., Keane M., Steinman R. M. Growth factor production and requirements during the proliferative response of human T lymphocytes to anti-CD3 monoclonal antibody. J Immunol. 1989 Jun 15;142(12):4138–4143. [PubMed] [Google Scholar]
  15. Gray P. W., Goeddel D. V. Cloning and expression of murine immune interferon cDNA. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5842–5846. doi: 10.1073/pnas.80.19.5842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Huegin A. W., Cerny A., Hengartner H., Zinkernagel R. M. Suppression by cyclosporin A of murine T-cell-mediated immunity against viruses in vivo and in vitro. Cell Immunol. 1985 Feb;90(2):464–473. doi: 10.1016/0008-8749(85)90211-4. [DOI] [PubMed] [Google Scholar]
  17. June C. H., Ledbetter J. A., Gillespie M. M., Lindsten T., Thompson C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–4481. doi: 10.1128/mcb.7.12.4472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kashima N., Nishi-Takaoka C., Fujita T., Taki S., Yamada G., Hamuro J., Taniguchi T. Unique structure of murine interleukin-2 as deduced from cloned cDNAs. 1985 Jan 31-Feb 6Nature. 313(6001):402–404. doi: 10.1038/313402a0. [DOI] [PubMed] [Google Scholar]
  19. Kroczek R. A., Black C. D., Barbet J., Shevach E. M. Mechanism of action of cyclosporin A in vivo. I. Cyclosporin A fails to inhibit T lymphocyte activation in response to alloantigens. J Immunol. 1987 Dec 1;139(11):3597–3603. [PubMed] [Google Scholar]
  20. 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]
  21. Laing T. J., Weiss A. Evidence for IL-2 independent proliferation in human T cells. J Immunol. 1988 Feb 15;140(4):1056–1062. [PubMed] [Google Scholar]
  22. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  24. Miyawaki T., Yachie A., Ohzeki S., Nagaoki T., Taniguchi N. Cyclosporin A does not prevent expression of Tac antigen, a probable TCGF receptor molecule, on mitogen-stimulated human T cells. J Immunol. 1983 Jun;130(6):2737–2742. [PubMed] [Google Scholar]
  25. Reed J. C., Abidi A. H., Alpers J. D., Hoover R. G., Robb R. J., Nowell P. C. Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression. J Immunol. 1986 Jul 1;137(1):150–154. [PubMed] [Google Scholar]
  26. Ryffel B., Feurer C., Heuberger B., Borel J. F. Immunosuppressive effect of cyclosporin A in two lymphocyte transfer models in rats: comparison of in vivo and in vitro treatment. Immunobiology. 1982 Dec;163(5):470–483. doi: 10.1016/S0171-2985(82)80061-2. [DOI] [PubMed] [Google Scholar]
  27. Shimuzu A., Kondo S., Takeda S., Yodoi J., Ishida N., Sabe H., Osawa H., Diamantstein T., Nikaido T., Honjo T. Nucleotide sequence of mouse IL-2 receptor cDNA and its comparison with the human IL-2 receptor sequence. Nucleic Acids Res. 1985 Mar 11;13(5):1505–1516. doi: 10.1093/nar/13.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tutschka P. J., Beschorner W. E., Hess A. D., Santos G. W. Cyclosporin-A to prevent graft-versus-host disease: a pilot study in 22 patients receiving allogeneic marrow transplants. Blood. 1983 Feb;61(2):318–325. [PubMed] [Google Scholar]
  29. White D. J., Calne R. Y. The use of Cyclosporin A immunosuppression in organ grafting. Immunol Rev. 1982;65:115–131. doi: 10.1111/j.1600-065x.1982.tb00430.x. [DOI] [PubMed] [Google Scholar]
  30. Zipfel P. F., Irving S. G., Kelly K., Siebenlist U. Complexity of the primary genetic response to mitogenic activation of human T cells. Mol Cell Biol. 1989 Mar;9(3):1041–1048. doi: 10.1128/mcb.9.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES