Paradoxical derepression of collagenase gene expression by the antirheumatic gold compound aurothiomalate.
The neutral metalloproteinase collagenase is known to be, among others, one of the key enzymes promoting joint destruction in patients with rheumatoid arthritis. Because inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-alpha, are considered to activate collagenase gene expression through activation of the transcription factor activator protein-1, we examined whether the water-soluble gold compound aurothiomalate (AuTM) influenced collagenase gene expression, using phorbol ester-treated human fibroblasts. However, AuTM did not prevent phorbol ester-mediated activation of activator protein-1 DNA-binding activity and subsequent induction of collagenase gene expression. In contrast, AuTM counteracted the repressive effects of glucocorticoids on collagenase gene expression and restored collagenase mRNA levels. The molecular target of this paradoxical AuTM action was suggested to be the glucocorticoid receptor.
Makino
Y
Y
Second Department of Internal Medicine, Asahikawa Medical College, Japan.
Tanaka
H
H
Makino
I
I
D000328:Adult; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D005938:Glucocorticoids; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D006052:Gold Sodium Thiomalate; D017364:Collagenases; D013755:Tetradecanoylphorbol Acetate