Induction of rapid IL-1 beta mRNA degradation in THP-1 cells mediated through the AU-rich region in the 3'UTR by a radicicol analogue

A radicicol analogue (analogue A) was found to inhibit interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) secretion from THP-1 cells. If added to cells activated by interferon gamma and lipopolysaccharide, radicicol analogue A not only inhibited the secretion of IL-1 beta bu...

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Bibliographic Details
Published in:Cytokine (Philadelphia, Pa.) Pa.), 1996-10, Vol.8 (10), p.751-761
Main Authors: Kastelic, T, Schnyder, J, Leutwiler, A, Traber, R, Streit, B, Niggli, H, MacKenzie, A, Cheneval, D
Format: Article
Language:English
Subjects:
Base Sequence
Cloning, Molecular
Cycloheximide - pharmacology
Dactinomycin - pharmacology
Enzyme-Linked Immunosorbent Assay
Humans
Interleukin-1 - genetics
Interleukin-1 - metabolism
Lactones - chemistry
Lactones - pharmacology
Lipopolysaccharides - pharmacology
Macrolides
Molecular Sequence Data
Polymerase Chain Reaction
RNA, Messenger - metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:A radicicol analogue (analogue A) was found to inhibit interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha) secretion from THP-1 cells. If added to cells activated by interferon gamma and lipopolysaccharide, radicicol analogue A not only inhibited the secretion of IL-1 beta but also induced an extremely rapid degradation of IL-1 beta, IL-6 and TNF-alpha mRNA to undetectable levels within 5-8 h. This degradation is independent of translation and of the signal inducing transcription. The common feature of these genes is the inclusion of one or more copies of the mRNA-instability sequence, AUUUA, in the 3' untranslated region. Indeed, no destabilizing effect of radicicol analogue A could be observed on mRNA derived from the expression of an IL-1 beta construct lacking the AUUUA motifs of the 3'UTR. The effect of radicicol analogue A on protein/mRNA interaction and on post-translational modifications of cytoplasmic proteins is described. This class of compound constitutes a valuable tool for the further elucidation of the mechanism of mRNA degradation of cytokines and proto-oncogenes.
ISSN:1043-4666
DOI:10.1006/cyto.1996.0100