Role of Transcriptional Activation of IκBα in Mediation of Immunosuppression by Glucocorticoids

• Published in: Science (American Association for the Advancement of Science) Vol. 270; no. 5234; pp. 283 - 286
• Main Authors: Scheinman, Robert I., Cogswell, Patricia C., Lofquist, Alan K., Baldwin, Albert S.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 13.10.1995; American Association for the Advancement of Science
• Subjects: Actins; Antibodies; Biological and medical sciences; Cell Line; Cell Nucleus - metabolism; Cytokines; Dexamethasone - pharmacology; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Genes; HeLa Cells; Humans; I-kappa B Proteins; Immunosuppression; Immunosuppressive Agents - pharmacology; Lipopolysaccharides - pharmacology; Messenger RNA; Molecular and cellular biology; Molecular genetics; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Protein synthesis; rev genes; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Transcription Factor RelA; Transcription, Genetic - drug effects; Transcription. Transcription factor. Splicing. Rna processing; Tumor Necrosis Factor-alpha - pharmacology; Vertebrata; Immunosuppression; Regulation(control); Dexamethasone; Mammalia; Transcription; Steroid hormone; Immunosuppressive agent; Transcription factor NFκB; Gene expression; Mechanism of action; Glucocorticoid
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.270.5234.283

Glucocorticoids are potent immunosuppressive drugs, but their mechanism is poorly understood. Nuclear factor kappa B (NF-κB), a regulator of immune system and inflammation genes, may be a target for glucocorticoid-mediated immunosuppression. The activation of NF-κB involves the targeted degradation of its cytoplasmic inhibitor, IκBα, and the translocation of NF-κB to the nucleus. Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IκBα gene, which results in an increased rate of IκBα protein synthesis. Stimulation by tumor necrosis factor causes the release of NF-κB from IκBα. However, in the presence of dexamethasone this newly released NF-κB quickly reassociates with newly synthesized IκBα, thus markedly reducing the amount of NF-κB that translocates to the nucleus. This decrease in nuclear NF-κB is predicted to markedly decrease cytokine secretion and thus effectively block the activation of the immune system.