Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB.

Previously a novel gene was identified that encodes a glucocorticoid-induced leucine zipper (GILZ) whose expression is up-regulated by dexamethasone. This study analyzed the role of GILZ in the control of T-cell activation and its possible interaction with nuclear factor kappaB (NF-kappaB). Results indicate that GILZ inhibits both T-cell receptor (TCR)-induced interleukin-2/interleukin-2 receptor expression and NF-kappaB activity. In particular, GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. Moreover, GILZ-mediated modulation of TCR-induced responses is part of a circuit because TCR triggering down-regulates GILZ expression. These results identify a new molecular mechanism involved in the dexamethasone-induced regulation of NF-kappaB activity and T-cell activation. (Blood. 2001;98:743-753)

[1]  C. Riccardi,et al.  Glucocorticoid hormone-induced modulation of gene expression and regulation of T-cell death: role of GITR and GILZ, two dexamethasone-induced genes , 1999, Cell Death and Differentiation.

[2]  D. Baltimore,et al.  Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. , 1999, Immunity.

[3]  Y. Tao,et al.  NF-κB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type , 1999, Cell Death and Differentiation.

[4]  C. Riccardi,et al.  Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. , 1999, Blood.

[5]  R. Schwartz,et al.  Molecular regulation of interleukin‐2 expression by CD28 co‐stimulation and anergy , 1998, Immunological reviews.

[6]  S. Ju,et al.  Identification of two NF-kappa B sites in mouse CD95 ligand (Fas ligand) promoter: functional analysis in T cell hybridoma. , 1998, Journal of immunology.

[7]  C. Y. Wang,et al.  NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. , 1998, Science.

[8]  E. Palmer,et al.  Positive Selection Through a Motif in the αβ T Cell Receptor , 1998 .

[9]  J. Ashwell,et al.  Cyclosporin A-Sensitive Transcription Factor Egr-3 Regulates Fas Ligand Expression , 1998, Molecular and Cellular Biology.

[10]  S. Gerondakis,et al.  The regulation and roles of Rel/NF-kappa B transcription factors during lymphocyte activation. , 1998, Current opinion in immunology.

[11]  J. Tschopp,et al.  Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. , 1998, Immunity.

[12]  D. Green,et al.  DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1. , 1998, Molecular cell.

[13]  W. Fiers,et al.  Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Riccardi,et al.  A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. , 1997, Immunity.

[15]  M. Guo,et al.  Role of the Fas/Fas ligand pathway in apoptotic cell death induced by the human T cell lymphotropic virus type I Tax transactivator. , 1997, The Journal of general virology.

[16]  J. Leiden,et al.  LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. , 1997, Science.

[17]  D. Green,et al.  Fas-ligand: privilege and peril. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Riccardi,et al.  A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Boothby,et al.  Perturbation of the T Lymphocyte Lineage In Transgenic Mice Expressing a Constitutive Repressor of Nuclear Factor (NF)-κB , 1997, The Journal of experimental medicine.

[20]  C. Riccardi,et al.  CD2 rescues T cells from T-cell receptor/CD3 apoptosis: a role for the Fas/Fas-L system. , 1997, Blood.

[21]  E. Harhaj,et al.  Regulation of the interleukin-2 CD28-responsive element by NF-ATp and various NF-kappaB/Rel transcription factors , 1997, Molecular and cellular biology.

[22]  Craig B. Thompson,et al.  Hierarchical Control of Lymphocyte Survival , 1996, Science.

[23]  S. Grimm,et al.  Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis , 1996, The Journal of cell biology.

[24]  D. Margulies,et al.  A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. , 1995, Immunity.

[25]  S. Minucci,et al.  Efficient Inhibition of Activation-induced Fas Ligand Up-regulation and T Cell Apoptosis by Retinoids Requires Occupancy of both Retinoid X Receptors and Retinoic Acid Receptors (*) , 1995, The Journal of Biological Chemistry.

[26]  G. Chrousos,et al.  The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. , 1995, The New England journal of medicine.

[27]  C. Ware,et al.  Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids , 1995, The Journal of experimental medicine.

[28]  T. Yokota,et al.  Expression of the Fas ligand in cells of T cell lineage. , 1995, Journal of immunology.

[29]  J. Gustafsson,et al.  Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. , 1995, Molecular endocrinology.

[30]  S. Ju,et al.  Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation , 1995, Nature.

[31]  P. Krammer,et al.  Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) , 1995, Nature.

[32]  J. Cidlowski,et al.  Characterization of mechanisms involved in transrepression of NF-kappa B by activated glucocorticoid receptors , 1995, Molecular and cellular biology.

[33]  C. Smith,et al.  Fas ligand mediates activation-induced cell death in human T lymphocytes , 1995, The Journal of experimental medicine.

[34]  V. Papadopoulos,et al.  Steroid production in the thymus: implications for thymocyte selection , 1994, The Journal of experimental medicine.

[35]  A. Neri,et al.  Mechanism of expression and role in transcriptional control of the proto-oncogene NFKB-2/LYT-10. , 1994, Oncogene.

[36]  A. Ray,et al.  Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[37]  I. Adcock,et al.  Anti-inflammatory actions of steroids: molecular mechanisms. , 1993, Trends in pharmacological sciences.

[38]  V. Bours,et al.  The oncoprotein Bcl‐3 can facilitate NF‐kappa B‐mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. , 1993, The EMBO journal.

[39]  T. Pohl,et al.  Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. , 1993, Immunology today.

[40]  Hoffman Gs.  Immunosuppressive therapy for autoimmune diseases. , 1993 .

[41]  V. Bours,et al.  The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers , 1993, Cell.

[42]  W. Paul,et al.  The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice , 1992, The Journal of experimental medicine.

[43]  S. Schreiber.  Immunophilin-sensitive protein phosphatase action in cell signaling pathways , 1992, Cell.

[44]  M. Raff,et al.  Social controls on cell survival and cell death , 1992, Nature.

[45]  M. Iwata,et al.  Rescue of thymocytes and T cell hybridomas from glucocorticoid‐induced apoptosis by stimulation via the T cell receptor/CD3 complex: a possible in vitro model for positive selection of the T cell repertoire , 1991, European journal of immunology.

[46]  P. Linsley,et al.  Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation , 1991, The Journal of experimental medicine.

[47]  B. Sander,et al.  Assessment of Cytokines by Immunofluorescence and the Paraformaldehyde‐Saponin Procedure , 1991, Immunological reviews.

[48]  J. Sprent,et al.  Extrathymic tolerance of mature T cells: Clonal elimination as a consequence of immunity , 1990, Cell.

[49]  M. Merćep,et al.  Programmed T lymphocyte death. Cell activation- and steroid-induced pathways are mutually antagonistic. , 1990, Journal of immunology.

[50]  M. Nieto,et al.  IL-2 protects against anti-CD3-induced cell death in human medullary thymocytes. , 1990, Journal of immunology.

[51]  H. Macdonald,et al.  Programmed death of autoreactive thymocytes , 1990, Nature.

[52]  C A Smith,et al.  Antigen‐induced apoptosis in developing t cells: a mechanism for negative selection of the t cell receptor repertoire* , 1989, European journal of immunology.

[53]  G. Crabtree.  Contingent genetic regulatory events in T lymphocyte activation. , 1989, Science.

[54]  J. Cohen,et al.  Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. , 1984, Journal of immunology.

[55]  H. Grey,et al.  Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing , 1983, The Journal of experimental medicine.

[56]  A. Fauci,et al.  Corticosteroid‐Mediated Immunoregulation in Man , 1982, Immunological reviews.

[57]  A. Wyllie.  Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation , 1980, Nature.

[58]  J. Harmon,et al.  Glucocorticoid-induced apoptosis and regulation of NF-kappaB activity in human leukemic T cells. , 1998, Endocrinology.

[59]  D. Baltimore,et al.  Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. , 1995, Nature.

[60]  M. Karin,et al.  Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. , 1995, Science.

[61]  A. Rao,et al.  Transcriptional regulation of the IL-2 gene. , 1995, Current opinion in immunology.

[62]  A. Baldwin,et al.  Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. , 1995, Science.

[63]  G. Migliorati,et al.  Dexamethasone induces apoptosis in mouse natural killer cells and cytotoxic T lymphocytes. , 1994, Immunology.

[64]  C. Riccardi,et al.  Interleukin-4 protects double-negative and CD4 single-positive thymocytes from dexamethasone-induced apoptosis. , 1993, Blood.

[65]  G. Hoffman.  Immunosuppressive therapy for autoimmune diseases. , 1993, Annals of allergy.

[66]  D. Longo,et al.  Cancer chemotherapy and biological response modifiers annual , 1987 .