Immunosuppression by Glucocorticoids: Inhibition of NF-κB Activity Through Induction of IκB Synthesis

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-κB) activation in mice and cultured cells. This inhibition is mediated by induction of the IκBα inhibitory protein, which traps activated NF-κB in inactive cytoplasmic complexes. Because NF-κB activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.

[1]  A. Baldwin,et al.  Role of Transcriptional Activation of IκBα in Mediation of Immunosuppression by Glucocorticoids , 1995, Science.

[2]  A. Yaron,et al.  In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B , 1995, Molecular and cellular biology.

[3]  M. Karin,et al.  Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B , 1995, Molecular and cellular biology.

[4]  H. Erdjument-Bromage,et al.  IκB-β regulates the persistent response in a biphasic activation of NF-κB , 1995, Cell.

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

[6]  P. Baeuerle,et al.  A proteasome inhibitor prevents activation of NF‐kappa B and stabilizes a newly phosphorylated form of I kappa B‐alpha that is still bound to NF‐kappa B. , 1994, The EMBO journal.

[7]  S. Ghosh,et al.  Inhibition of NF-kappa B by sodium salicylate and aspirin. , 1994, Science.

[8]  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.

[9]  A. Baldwin,et al.  The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. , 1993, Genes & development.

[10]  M. Pfahl.  Nuclear receptor/AP-1 interaction. , 1993, Endocrine reviews.

[11]  W. Greene,et al.  Cross‐coupling of the NF‐kappa B p65 and Fos/Jun transcription factors produces potentiated biological function. , 1993, The EMBO journal.

[12]  M. Karin,et al.  NF-kappa B activation by ultraviolet light not dependent on a nuclear signal. , 1993, Science.

[13]  Y. Ben-Neriah,et al.  Rapid proteolysis of IκB-α is necessary for activation of transcription factor NF-κB , 1993, Nature.

[14]  R. Taub,et al.  I kappa B alpha can localize in the nucleus but shows no direct transactivation potential. , 1993, Oncogene.

[15]  F. Bach,et al.  Cytokine‐inducible expression in endothelial cells of an I kappa B alpha‐like gene is regulated by NF kappa B. , 1993, The EMBO journal.

[16]  G. Kroemer,et al.  Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo , 1993, The Journal of experimental medicine.

[17]  M. Karin,et al.  p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. , 1993, Genes & development.

[18]  W C Greene,et al.  NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. , 1993, Science.

[19]  K. Kaushansky,et al.  Transcriptional regulation of interleukin 3 (IL3) in primary human T lymphocytes. Role of AP-1- and octamer-binding proteins in control of IL3 gene expression. , 1993, The Journal of biological chemistry.

[20]  G. Franzoso,et al.  Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. F. Shannon,et al.  The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[22]  I. G. Young,et al.  Sex hormones and dexamethasone modulate interleukin-5 gene expression in T lymphocytes , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[23]  U. Zabel,et al.  Nuclear uptake control of NF‐kappa B by MAD‐3, an I kappa B protein present in the nucleus. , 1993, The EMBO journal.

[24]  M. Grilli,et al.  NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. , 1993, International review of cytology.

[25]  G. Crabtree,et al.  Negative regulation of interleukin 2 transcription by the glucocorticoid receptor , 1992, The Journal of experimental medicine.

[26]  C. Langlet,et al.  Evidence for quantitative and qualitative differences in functional activation of MIs‐reactive T cell clones and hybridomas by antigen or TcR/CD3 antibodies , 1991, European journal of immunology.

[27]  S. Haskill,et al.  Characterization of an immediate-early gene induced in adherent monocytes that encodes IκB-like activity , 1991, Cell.

[28]  P. Baeuerle.  The inducible transcription activator NF-κB: regulation by distinct protein subunits , 1991 .

[29]  W. Fiers,et al.  Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: prevention by high doses of methylprednisolone. , 1991, Journal of immunology.

[30]  M. Karin,et al.  Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction , 1990, Cell.

[31]  Stephan Gebel,et al.  Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone , 1990, Cell.

[32]  K. Yamamoto,et al.  Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. , 1990, Science.

[33]  U. Zabel,et al.  Purified human IκB can rapidly dissociate the complex of the NF-κB transcription factor with its cognate DNA , 1990, Cell.

[34]  M. von Knebel Doeberitz,et al.  Glucocorticoid hormones reduce the expression of major histocompatibility class I antigens on human epithelial cells , 1990, European journal of immunology.

[35]  G. Crabtree,et al.  Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. , 1990, Annual review of immunology.

[36]  T. Strom,et al.  Evidence that glucocorticosteroids block expression of the human interleukin-6 gene by accessory cells. , 1990, Transplantation.

[37]  I. Screpanti,et al.  Tumor-promoting phorbol ester and ras oncogene expression inhibit the glucocorticoid-dependent transcription from the mouse mammary tumor virus long terminal repeat. , 1989, Molecular endocrinology.

[38]  M. Beato.  Gene regulation by steroid hormones , 1989, Cell.

[39]  M. Karin,et al.  Ubiquitous and lymphocyte‐specific factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes. , 1989, The EMBO journal.

[40]  D. Baltimore,et al.  I kappa B: a specific inhibitor of the NF-kappa B transcription factor. , 1988, Science.

[41]  J D Baxter,et al.  Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer. , 1988, Science.

[42]  D. Baltimore,et al.  Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-κB transcription factor , 1988, Cell.

[43]  T. Strom,et al.  Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. , 1987, Journal of immunology.

[44]  D. Belin,et al.  Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription. , 1987, Journal of immunology.

[45]  J. Bluestone,et al.  Identification of a monoclonal antibody specific for a murine T3 polypeptide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[46]  B. Beutler,et al.  Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. , 1986, Science.

[47]  J. Culpepper,et al.  Regulation of IL 3 expression by glucocorticoids in cloned murine T lymphocytes. , 1985, Journal of immunology.

[48]  S. Arya,et al.  Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. , 1984, Journal of immunology.

[49]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[50]  M. M. Garner,et al.  A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system , 1981, Nucleic Acids Res..

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

[52]  A. Fauci,et al.  Mechanisms of glucocorticoid action on immune processes. , 1979, Annual review of pharmacology and toxicology.