[Mechanisms of glucocorticoid sensitivity modulation by cytokines].
We have previously shown that TNF-alpha and IL-1 may enhance the glucocorticoid (GC)-induced transcriptional activity of glucocorticoid receptor (GR) in different cell lines transfected with a reporter plasmid carrying GC response elements (GRE). In TNF-alpha and GC target cell lines, it was found that: 1) TNF-alpha enhanced GR number in L-929 cells, and 2) by transfection of these cells with a reporter plasmid carrying the GR promoter, that TNF-alpha-induced increase in GR is at the transcriptional level, 3) by electrophoretic mobility shift assay, using nuclear extracts of TNF-alpha (0.02 ng/ml) or TNF-alpha plus DEX (10 nM) stimulated L-929 cells, that cytokines can increase the binding of GR to GRE (45 min, 1.8 x), while the TNF-alpha-induced NFkB factor expression was not affected by GC. 4) As a biological correlate of this mechanism, priming of L-929 cells with TNF-alpha significantly increased (p < 0.001) the sensitivity to GC inhibition of TNF-alpha-induced apoptosis. The organism protects itself from an immune overreaction, not only via the HPA axis induction and an increase in GC by cytokines, but also enhancing the sensitivity to GC: by an increase in GR number, the binding to GRE and the transcription of GC target genes (e.g. TNF-alpha-induced apoptosis inhibitory genes). These mechanisms contribute to enhance the immunosuppressive and antiinflammatory GC activity, in order to maintain homeostasis.
Costas
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Instituto de Investigaciones Médicas Alfredo Lanari, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
Kovalovsky
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Arzt
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D017209:Apoptosis; D016207:Cytokines / Q000502:physiology*; D005938:Glucocorticoids / Q000502:physiology*; D006706:Homeostasis; D007375:Interleukin-1 / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D005938:Glucocorticoids; D007375:Interleukin-1; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha