Molecular mechanisms of steroid action: a novel type of cross-talk between glucocorticoids and NF-kappa B transcription factors.
Despite the widespread use of glucocorticoids in the treatment of diseases characterized by inflammation, the molecular mechanism(s) by which these hormones exert this beneficial effect in patients with asthma remains to be elucidated. Therefore, we have studied the transcriptional regulation of intercellular adhesion molecule-1 (ICAM-1) as adhesion molecules are likely to play a causal role in inflammation in promoting cell-cell and cell-matrix interactions. We observed that in a monocytic (U937) and a bronchial epithelial (H292) cell-line dexamethasone strongly suppressed basal and induced ICAM-1 expression. Subsequent analysis of the human ICAM-1 promoter has revealed that both 12-O-tetradecanoylphorbol 13-acetate (TPA) and tumour necrosis factor-alpha (TNF-alpha) upregulate ICAM-1 expression through the presence of a nuclear factor (NF-kappa B) target sequence (TGGAAATTCC). No glucocorticoid recognition sequences are present in this promoter region and dexamethasone is still able to repress transcription when the multimerized NF-kappa B sequence is transactivated by TNF-alpha upon transfection in 293 cells. We propose that direct interaction between the glucocorticoid receptor and nuclear factor-kappa B factors is at least a partial explanation for the effects of this hormone in inflammatory diseases.
van der Saag
P T
PT
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, The Netherlands.
Caldenhoven
E
E
van de Stolpe
A
A
D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate