Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor.
The glucocorticoid receptor (GR) acts both as a transcription factor itself on genes carrying GR response elements (GREs) and as a modulator of other transcription factors. Using mice with a mutation in the GR, which cannot activate GRE promoters, we examine whether the important anti-inflammatory and immune suppressive functions of glucocorticoids (GCs) can be established in this in vivo animal model. We find that most actions are indeed exerted in the absence of the DNA-binding ability of the GR: inhibition of the inflammatory response of locally irritated skin and of the systemic response to lipopolysaccharides. GCs repress the expression and release of numerous cytokines both in vivo and in isolated primary macrophages, thymocytes and CD4(+) splenocytes. A transgenic reporter gene controlled by NF-kappa B exclusively is also repressed, suggesting that protein- protein interaction with other transcription factors such as NF-kappa B forms the basis of the anti-inflammatory activity of GR. The only defect of immune suppression detected so far concerns the induced apoptosis of thymocytes and T lymphocytes.
Reichardt
H M
HM
Division of Molecular Biology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Tuckermann
J P
JP
Göttlicher
M
M
Vujic
M
M
Weih
F
F
Angel
P
P
Herrlich
P
P
Schütz
G
G
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism* / Q000502:physiology
D016207:Cytokines; D017931:DNA Primers; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D004247:DNA