Summary
Glucocorticoid hormones, calcium ionophores and anti-CD3 monoclonal antibodies induce apoptosis in mouse thymocytes. This type of cell death, which is characterized by an extensive DNA fragmentation into oligonucleosomal subunits, occurs in the intrathymic process of negative selection, and is involved in the deletion of autoreactive T-cells during thymic maturation. A number of cytokines are able to modulate apoptosis, and interleukins, including interleukin-1, interleukin-2, and interleukin-4, play a crucial role in thymic maturation and T-cell development. We tested the effects of several cytokines on the glucocorticoid hormone-induced apoptosis of mouse thymocytes in vitro, and demonstrated that interleukin-1α, interleukin-2, and interleukin-4 inhibit the apoptosis induced by dexamethasone, but that interleukin-3 and interleukin-6 exert no noteworthy effect. Dose-response experiments indicated that interleukin-4 is more potent than interleukin-1α and interleukin-2 in inhibiting dexamethasone-induced apoptosis. Furthermore, interleukin-4 fully inhibited the DNA fragmentation induced by the protein kinase-C activator 12-O-tetradecanoylphorbol-13-acetate, but was ieffective against apoptosis induced by the calcium ionophore A23187. These results suggest that interleukins regulate the thymic selection process by acting as modulators of the negative selection process.
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Barcena A, Toribio ML, Pezzi L, Martinez-A C, A role for interleukin 4 in the differentiation of mature T cell receptor gamma/delta+cells from human intrathymic T cell precursors. J Exp Med 172: 439, 1990
Brown M, Hu-li J, Paul WE, IL-4/B cell stimulating factor 1 stimulates T-cell growth by an IL-2-independent mechanism. J Immunol 131: 504, 1988
Cohen JJ, Duke RC, Glucocorticoid activation of a calcium dependent endonuclease in thymocyte nucleic leads to cell death. J Immunol 132: 38, 1984
Fernandez-Ruiz E, Rebollo A, Nieto MA, Sanz E, Somoza C, Ramirez F, Lopez-Rivas A, Silva A, IL-2 protects T cell hybrids from cytolytic effect of glucocorticoids. Synergistic effect of IL-2 and dexamethasone in the induction of high-affinity IL-2 receptors. J Immunol 143: 4146, 1989
Jenkinson EJ, Kingston R, Smith CA, Williams GT, Owen JJT, Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell repertoire. Eur J Immunol 20: 2517, 1990
Kappler JW, Roehm N, Marrak P, T-cell tolerance by clonal elimination in the thymus. Cell 49: 273, 1987
Lawetzky A, Kubbies M, Hunig T, Rat “first wave” mature thymocytes: cycling lymphoblasts that are sensitive to activation-induced cell death but rescued by interleukin-2. Eur J Immunol 21: 2599, 1991
McConkey DJ, Hartzell P, Nicotera S, Orrenius S, Jondal M, Calcium-dependent killing of immature thymocytes by stimulation via CD3/T cell receptor complex. J Immunol 143: 1801, 1989
McConkey DJ, Hartzell P, Chow SC, Orrenius S, Jondal M, Interleukin 1 inhibits T cell receptor-mediated apoptosis in immature thymocytes. J Biol Chem 265: 3009, 1990
Nicoletti I, Miglirati G, Pagliacci MC, Grignani F, Riccardi C, A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271, 1991
Nieto MA, Lopez-Rivas A, IL-2 protects T lymphocytes from glucocorticoid-induced DNA fragmentation and cell death. J Immunol 143: 4166, 1989
Nieto M, Gonzales A, Lopez-Rivas A, Diaz-Espada F, Gambon F, IL-2 protects against anti-CD3-induced cell death in human medullary thymocytes. J Immunol 145: 1364, 1990
Ojeda F, Guarda MI, Maldonado C, Folch U, Protein kinase-C involvement in thymocyte apoptosis induced by hydrocortisone. Cell Immunol 125: 535, 1990
Palacios R, Sideras P, Von Boehmer H, Recombinant interleukin-4/BSF-1 promotes growth and differentiation of intrathymic T cell precursors from fetal mice in vitro. EMBO J 6: 91, 1987
Sei Y, Yoshimoto K, McIntyre T, Skolnick P, Arora PK, Morphine-induced thymic hypoplasia is glucocorticoid-dependent. J Immunol 146: 194, 1991
Shi Y, Sahai BM, Green DR, Cyclosporin A inhibits activation-induced cell death in T cell hybridomas and thymocytes. Nature 339: 625, 1989
Sideras P, Funa K, Zalcberg-Quintana I, Xanthopoulos KG, Kisielow P, Palacios R, Analysis by in situ hybridization of cell expressing mRNA for interleukin 4 in the developing thymus and in the peripheral lymphocytes from mice. Proc Natl Acad Sci USA 85: 218, 1988
Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJT, Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 337: 181, 1989
Sprent J, Lo D, Gao E, Ron Y, T cell selection in the thymus. Immunol Rev 101: 173, 1988
Von Boehmer H, Teh HS, Kisielow P, The thymus selects the useful, neglects the useless and destroys the harmful. Immunol Today 10: 57, 1989
Willie AH, Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555, 1980
Willie AH, Kerr JFR, Currie AR, Cell death: the significance of apoptosis. Int Rev Cytol 68: 251, 1980
Willie AH, Morris GR, Smith AL, Dunlop D, Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol 142: 67, 1984
Zinkernagel RM, Thymuses nd lymphohemopoietic cells. Maturation in selection of T cells, H-2 restriction specificity and H-2 linked Ir gene control. Immunol Rev 42: 224, 1978
Zircher H, Rohrer UH, Moskophidis D, zinkernagel RM, Hengartner H, Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351: 1482, 1991
Zlotnik A, Ramson J, Frank G, Fischer M, Howard M, IL-4 is a growth factor for activated thymocytes: possible role in T-cell ontogeny. Proc Natl Acad Sci USA 84: 3856, 1987
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Migliorati, G., Pagliacci, C., Moraca, R. et al. Interleukins modulate glucocorticoid-induced thymocyte apoptosis. Int J Clin Lab Res 21, 300–303 (1992). https://doi.org/10.1007/BF02591666
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DOI: https://doi.org/10.1007/BF02591666