INDUCTION OF HUMAN INTERLEUKIN-1 GENE-EXPRESSION BY RETINOIC ACID ANDITS REGULATION AT PROCESSING OF PRECURSOR TRANSCRIPTS

Retinoic acid (RA), we show, induces in peripheral blood mononuclear c ells a transient wave of newly transcribed, unstable interleukin-1 alp ha (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 ta rgets for RA. Most IL-1 beta gene transcription induced by RA fails to yield mature mRNA. Instead, precursor transcripts accumulate, detecte d by ribonuclease protection analysis. The flow of precursors into IL- 1 beta mRNA becomes inhibited during induction. When translation is bl ocked, e.g. by cycloheximide, expression of IL-1 beta mRNA is superind uced by 2 orders of magnitude. Superinduction is dependent on transcri ption, yet is unaccompanied by increased primary transcription or mRNA stability. Instead, processing of unstable IL-1 beta precursor transc ripts into mature mRNA is greatly facilitated. Control is not narrowly localized within precursors: splicing of distinct exons and intron ex cision are enhanced by cycloheximide. Pre-mRNA processing thus is a li miting step in RA-induced IL-1 beta gene expression. This regulation i s specific for RA: when induced by phorbol ester, IL-1 beta gene expre ssion is also superinduced by cycloheximide but that response is accom panied by enhanced mRNA stability. Thus, IL-1 beta gene transcription is induced by RA, yet, unlike for other primary target genes, mRNA exp ression is regulated at pre-mRNA processing.