Abstract
The inhibitory effect of cyclosporin (CsA) was investigated on human lymphocytes stimulated by anti-T-cell antibodies (anti-CD3 and -CD2) or mitogenic lectins. Whereas inhibition of cell proliferation (50%) occurred at 10 ng/ml CsA after cell activation via CD3 or CD2, higher CsA concentrations (300 ng/ml) were necessary to inhibit lectin-mediated cell activation (PHA, Con A). Exogenous recombinant interleukin-2 (rIL-2) partially reversed the inhibitory effect on antibody-stimulated cells only; however, at higher CsA concentrations (300 ng/ml) proliferation was again inhibited. Thus, CsA affected IL-2R expression and/or function at higher concentrations (300 ng/ml). CsA had no effect on receptor function as measured on IL-2-dependent cell growth of CTLL cells or preactivated lymphocytes. However, CsA inhibited both high and low affinity receptor expression as shown by [125I]IL-2 equilibrium binding studies on anti-CD3-stimulated cells. Cross-linking studies revealed that both p55 (TAC) and p75 chains of the IL-2R were not induced at low CsA concentrations (10 ng/ml). However, addition of rIL-2 reversed CsA inhibition of IL-2R expression. It is concluded that CsA, at least in anti-CD3-stimulated cells, inhibits IL-2R expression and cell proliferation with similar potency. Exogenous rIL-2 reverses CsA inhibition of IL-2R expression. This might be due to binding of rIL-2 to receptors which escape CsA inhibition, thereby up-regulating receptor expression which is drug resistant.
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Selected References
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- Alcover A., Alberini C., Acuto O., Clayton L. K., Transy C., Spagnoli G. C., Moingeon P., Lopez P., Reinherz E. L. Interdependence of CD3-Ti and CD2 activation pathways in human T lymphocytes. EMBO J. 1988 Jul;7(7):1973–1977. doi: 10.1002/j.1460-2075.1988.tb03035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beveridge T. Clinical transplantation--overview. Prog Allergy. 1986;38:269–292. [PubMed] [Google Scholar]
- Bloemena E., Van Oers M. H., Weinreich S., Schellekens P. T. Cyclosporin A and prednisolone do not inhibit the expression of high-affinity receptors for interleukin 2. Clin Exp Immunol. 1988 Feb;71(2):308–313. [PMC free article] [PubMed] [Google Scholar]
- Bunjes D., Hardt C., Röllinghoff M., Wagner H. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol. 1981 Aug;11(8):657–661. doi: 10.1002/eji.1830110812. [DOI] [PubMed] [Google Scholar]
- Cantrell D. A., Collins M. K., Crumpton M. J. Autocrine regulation of T-lymphocyte proliferation: differential induction of IL-2 and IL-2 receptor. Immunology. 1988 Nov;65(3):343–349. [PMC free article] [PubMed] [Google Scholar]
- Depper J. M., Leonard W. J., Drogula C., Krönke M., Waldmann T. A., Greene W. C. Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4230–4234. doi: 10.1073/pnas.82.12.4230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dos Reis G. A., Shevach E. M. Effect of cyclosporin A on T cell function in vitro: the mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell. J Immunol. 1982 Dec;129(6):2360–2367. [PubMed] [Google Scholar]
- Dukovich M., Wano Y., Le thi Bich Thuy, Katz P., Cullen B. R., Kehrl J. H., Greene W. C. A second human interleukin-2 binding protein that may be a component of high-affinity interleukin-2 receptors. Nature. 1987 Jun 11;327(6122):518–522. doi: 10.1038/327518a0. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Gelfand E. W., Cheung R. K., Mills G. B. The cyclosporins inhibit lymphocyte activation at more than one site. J Immunol. 1987 Feb 15;138(4):1115–1120. [PubMed] [Google Scholar]
- 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]
- Harel-Bellan A., Bertoglio J., Quillet A., Marchiol C., Wakasugi H., Mishall Z., Fradelizi D. Interleukin 2 (IL 2) up-regulates its own receptor on a subset of human unprimed peripheral blood lymphocytes and triggers their proliferation. J Immunol. 1986 Apr 1;136(7):2463–2469. [PubMed] [Google Scholar]
- 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]
- Kanellopoulos J. M., De Petris S., Leca G., Crumpton M. J. The mitogenic lectin from Phaseolus vulgaris does not recognize the T3 antigen of human T lymphocytes. Eur J Immunol. 1985 May;15(5):479–486. doi: 10.1002/eji.1830150512. [DOI] [PubMed] [Google Scholar]
- Kaye J., Gillis S., Mizel S. B., Shevach E. M., Malek T. R., Dinarello C. A., Lachman L. B., Janeway C. A., Jr Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2. J Immunol. 1984 Sep;133(3):1339–1345. [PubMed] [Google Scholar]
- 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]
- 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]
- Meuer S. C., Hussey R. E., Cantrell D. A., Hodgdon J. C., Schlossman S. F., Smith K. A., Reinherz E. L. Triggering of the T3-Ti antigen-receptor complex results in clonal T-cell proliferation through an interleukin 2-dependent autocrine pathway. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1509–1513. doi: 10.1073/pnas.81.5.1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Reed J. C., Greene W. C., Hoover R. G., Nowell P. C. Monoclonal antibody OKT11A inhibits and recombinant interleukin 2 (IL 2) augments expression of IL 2 receptors at a pretranslational level. J Immunol. 1985 Oct;135(4):2478–2482. [PubMed] [Google Scholar]
- Robb R. J., Greene W. C., Rusk C. M. Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen. J Exp Med. 1984 Oct 1;160(4):1126–1146. doi: 10.1084/jem.160.4.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roosnek E. E., Brouwer M. C., Aarden L. A. T cell triggering by lectins. I. Requirements for interleukin 2 production; lectin concentration determines the accessory cell dependency. Eur J Immunol. 1985 Jul;15(7):652–656. doi: 10.1002/eji.1830150703. [DOI] [PubMed] [Google Scholar]
- Roosnek E. E., Brouwer M. C., Aarden L. A. T cell triggering by lectins. II. Stimuli for induction of interleukin 2 responsiveness and interleukin 2 production differ only in quantitative aspects. Eur J Immunol. 1985 Jul;15(7):657–661. doi: 10.1002/eji.1830150704. [DOI] [PubMed] [Google Scholar]
- Smith K. A., Cantrell D. A. Interleukin 2 regulates its own receptors. Proc Natl Acad Sci U S A. 1985 Feb;82(3):864–868. doi: 10.1073/pnas.82.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tagaya Y., Okada M., Sugie K., Kasahara T., Kondo N., Hamuro J., Matsushima K., Dinarello C. A., Yodoi J. IL-2 receptor(p55)/Tac-inducing factor. Purification and characterization of adult T cell leukemia-derived factor. J Immunol. 1988 Apr 15;140(8):2614–2620. [PubMed] [Google Scholar]
- 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]
- Tsudo M., Kozak R. W., Goldman C. K., Waldmann T. A. Contribution of a p75 interleukin 2 binding peptide to a high-affinity interleukin 2 receptor complex. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4215–4218. doi: 10.1073/pnas.84.12.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsudo M., Kozak R. W., Goldman C. K., Waldmann T. A. Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9694–9698. doi: 10.1073/pnas.83.24.9694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valentine M. A., Tsoukas C. D., Rhodes G., Vaughan J. H., Carson D. A. Phytohemagglutinin binds to the 20-kDa molecule of the T3 complex. Eur J Immunol. 1985 Aug;15(8):851–854. doi: 10.1002/eji.1830150821. [DOI] [PubMed] [Google Scholar]
- Weiss A., Imboden J., Hardy K., Manger B., Terhorst C., Stobo J. The role of the T3/antigen receptor complex in T-cell activation. Annu Rev Immunol. 1986;4:593–619. doi: 10.1146/annurev.iy.04.040186.003113. [DOI] [PubMed] [Google Scholar]