Induction of human interleukin-1 gene expression by retinoic acid and its regulation at processing of precursor transcripts.
Retinoic acid (RA), we show, induces in peripheral blood mononuclear cells a transient wave of newly transcribed, unstable interleukin-1 alpha (IL-1 alpha) and IL-1 beta mRNA. Tumor necrosis factor-alpha mRNA, by contrast, is expressed in multiple waves. IL-1 genes are primary targets for RA. Most IL-1 beta gene transcription induced by RA fails to yield mature mRNA. Instead, precursor transcripts accumulate, detected by ribonuclease protection analysis. The flow of precursors into IL-1 beta mRNA becomes inhibited during induction. When translation is blocked, e.g. by cycloheximide, expression of IL-1 beta mRNA is superinduced by 2 orders of magnitude. Superinduction is dependent on transcription, yet is unaccompanied by increased primary transcription or mRNA stability. Instead, processing of unstable IL-1 beta precursor transcripts into mature mRNA is greatly facilitated. Control is not narrowly localized within precursors: splicing of distinct exons and intron excision are enhanced by cycloheximide. Pre-mRNA processing thus is a limiting step in RA-induced IL-1 beta gene expression. This regulation is specific for RA: when induced by phorbol ester, IL-1 beta gene expression is also superinduced by cycloheximide but that response is accompanied by enhanced mRNA stability. Thus, IL-1 beta gene transcription is induced by RA, yet, unlike for other primary target genes, mRNA expression is regulated at pre-mRNA processing.
Jarrous
N
N
Department of Molecular Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Kaempfer
R
R
D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007375:Interleukin-1; D012322:RNA Precursors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014212:Tretinoin; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate