REGULATION OF INTERLEUKIN-1 BETA GENE EXPRESSION IN HUMAN MONOCYTES BY IL-4

IL-4是一种T细胞衍生的淋巴因子，具有强大的调节作用

IL-4 is a T cell-derived lymphokine that exerts potent regulatory effects on human monocytes. We have previously found that IL-4 significantly inhibits production of a number of LPS-inducible cytokines, including IL- 1, TNF and IL-6; however, it is not known how IL-4 suppresses cytokine synthesis. To determine whether IL-4 suppresses IL-1 expression by a transcriptional and/or posttranscriptional mechanism, we evaluated the half-life of LPS-induced IL-1beta message and transcriptional rate of the pro-IL-1beta gene in human monocytes following treatment with IL-4. Although the initial steady-state IL-1 mRNA levels in control and IL-4- treated monocytes were comparable during the first 2 hours following stimulation with LPS, IL-1 message levels subsequently decreased at a significantly greater rate in the IL-4-treated cells. Thus IL-4 did not prevent the initial expression of IL-1 message, but did accelerate down- regulation of IL-1 mRNA in LPS-stimulated monocytes. The initial 2-3 hour lag period may be necessary for production of a protein(s) which mediates this inhibitory effect because treatment with the protein synthesis inhibitor, cycloheximide, blocked the marked reduction of IL-1 message levels induced by IL-4. Nuclear run-on analyses demonstrated that IL-4 decreases IL-1 mRNA levels in part by repressing IL-1 gene transcription. Furthermore, mRNA half-life studies showed that IL-4 also significantly increases the rate of IL-1 message turnover in these cells. Together, these findings demonstrate that IL-4 inhibits IL-1 production in human monocytes by suppressing the formation of new IL-1 transcripts as well as by decreasing IL-1 message stability. In addition, the kinetics of inhibition and the fact that cycloheximide blocks this process suggest that IL-4 induces or enhances synthesis of a protein(s) which mediates these effects. In view of the fact that IL-4 inhibits synthesis of various proinflammatory cytokines, particularly IL-1, it may be worth evaluating the potential therapeutic effects of IL-4 in disease states characterized by excessive or unregulated expression of IL-1.