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-1α (IL-1α) and IL-1β mRNA. Tumor necrosis factor-α mRNA, by contrast, is expressed in multiple waves. IL-1 genes are primary targets for RA. Most IL-1β 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-1β mRNA becomes inhibited during induction. When translation is blocked, e.g. by cycloheximide, expression of IL-1β 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-1β 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-1β gene expression. This regulation is specific for RA: when induced by phorbol ester, IL-1β gene expression is also superinduced by cycloheximide but that response is accompanied by enhanced mRNA stability. Thus, IL-1β gene transcription is induced by RA, yet, unlike for other primary target genes, mRNA expression is regulated at pre-mRNA processing.