Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B 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-kappa B) activation in mice and cultured cells. This inhibition is mediated by induction of the I kappa B alpha inhibitory protein, which traps activated NF-kappa B in inactive cytoplasmic complexes. Because NF-kappa B 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.
Auphan
N
N
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla 92093-0636, USA.
DiDonato
J A
JA
Rosette
C
C
Helmberg
A
A
Karin
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006825:Hybridomas; D020672:I-kappa B Proteins; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007376:Interleukin-2; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate