THE 3'-UNTRANSLATED REGION OF IL-1-BETA REGULATES PROTEIN-PRODUCTION

IL-1 beta, a pro-inflammatory cytokine, has sequences in its 3' untran slated region (UTR) that may play a role in the post-transcriptional r egulation of IL-1 beta production. To test this hypothesis, a series o f chimeric reporter genes were developed consisting of a chloramphenic ol acetyltransferase (CAT) gene the native 3'-UTR of which was replace d by the full-length IL-1 beta 3'-UTR or various 3'-UTR deletion mutan ts. Expression of these constructs under the SV40 late promoter in THP -1 cells showed that the full-length 3'-UTR repressed constitutive CAT activity to 28% of control CAT activity. Further analysis of the 3'-U TR localized the repressor signal to an adenosine-thymidine (AdT)-rich region. Upon exposure to LPS, the full-length IL-1 beta 3'-UTR mediat ed almost a fivefold increase in CAT activity. The LPS response was no t simply loss of AdT-mediated repression; when this sequence was teste d alone, it did not respond to LPS. The LPS response effect was locali zed to the terminal 177 base pairs of the IL-1 beta 3'-UTR. The increa se in CAT activity following LPS stimulation was associated with an in creased CAT.IL-1 beta 3'-UTR mRNA half-life, indicating at least one e ffect of the 3'-UTR on a post-transcriptional process. These studies d emonstrate that the IL-1 beta 3'-UTR is involved in the regulation of IL-1 beta protein production, and a LPS response element may be in the IL-1 beta 3'-UTR.