Regulation of human synovial fibroblast collagenase messenger RNA by interleukin-1

Interleukin-1 (IL-1) may contribute to tissue destruction in rheumatoid arthritis, in part, by inducing messenger RNA (mRNA) that encodes interstitial collagenase. In human synovial fibroblasts in vitro, IL-1 induced collagenase mRNA accumulation 6 hours after being added to the cells. High levels of mRNA remained present for at least 48 hours after treatment. The rate of transcription of collagenase in isolated nuclei peaked after approximately 6 hours of treatment with IL-1 and declined thereafter, becoming nearly undetectable by 24 hours. The persistence of mRNA, in view of the transient peak of transcription, suggested that collagenase mRNA was stable in synovial fibroblasts. The half-life of collagenase mRNA after the synoviocytes were treated with actinomycin D was approximately 27 hours, both in the presence and in the absence of IL-1. It has been noted that induction of the expression of collagenase by phorbol esters requires fos protein synthesis and is mediated through a tetradecanoyl phorbol acetate response element in the 5'-flanking region of the gene. However, we found that cycloheximide, when added to synovial fibroblast cultures up to 6 hours after treatment with IL-1, inhibited the expression of collagenase mRNA. These results suggest that fos alone is unlikely to be sufficient for collagenase expression, and that additional factors, or alternative pathways, are involved in the induction of collagenase by IL-1.