Abstract
Repression of NFkappaB-dependent gene expression is one of the major elements of immunosuppression by glucocorticoids. Protein-protein interactions between the glucocorticoid receptor and NFkappaB have been characterized and shown to be a possible mechanism of mutual inhibition of transactivation properties. More recently, glucocorticoid-mediated induction of IkappaBalpha, an inhibitor of NFkappaB, has been described in monocytes and lymphocytes; an increase in IkappaBalpha mRNA and protein resulted in inactivation and cytosolic retention of NFkappaB. Thus, rather than the physical interaction between the glucocorticoid receptor and NFkappaB, the up-regulation of IkappaBalpha was presented as the key element in immunosuppression by glucocorticoids. In contrast, we show that the IkappaBalpha pathway is not involved in glucocorticoid-mediated inhibition of NFkappaB activity in endothelial cells. Although transcriptional activation by NFkappaB was significantly reduced in the presence of glucocorticoids, we did not detect induction of IkappaBalpha protein that could prevent nuclear translocation of NFkappaB upon stimulation with lipopolysaccharide or tumor necrosis factor alpha. Furthermore, treatment with glucocorticoids did not seem to affect the transcription rate or mRNA stability of IkappaBalpha. We therefore conclude that, although induction of IkappaBalpha expression by glucocorticoids seems to be of importance in monocytes and lymphocytes, it cannot explain inhibition of NFkappaB-dependent gene expression in endothelial cells. Our results emphasize the relevance of physical interaction between the glucocorticoid receptor and NFkappaB in endothelial cells and thus in suppression of inflammation by glucocorticoids.
Highlights
Glucocorticoids are potent immunosuppressive agents [1] with the potential to inhibit expression of several cytokines and adhesion molecules involved in inflammatory immune responses [2,3,4,5,6,7,8]
Transcriptional repression by the glucocorticoid receptor (GR) may be based on proteinprotein interactions between the GR and other transcription factors, without the requirement for DNA binding by the GR [15]
We conclude that induction of IB␣ synthesis by DEX may play a crucial role in preventing NFB activation in monocytes and T lymphocytes, it cannot account for glucocorticoidmediated repression of NFB-dependent gene expression in endothelial cells, which emphasizes the importance of proteinprotein interactions between NFB and the GR in immunosuppression
Summary
Glucocorticoids are potent immunosuppressive agents [1] with the potential to inhibit expression of several cytokines and adhesion molecules involved in inflammatory immune responses [2,3,4,5,6,7,8]. Induction of cytokine gene expression is mostly dependent on the activation of the transcription factors AP1 and/or NFB, both of which have been shown to interact physically with the GR, resulting in mutual inhibition of DNA binding and transactivation properties (16 –22).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.