IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4.
The T cell-derived lymphokine, IL-4, inhibits production of IL-1 beta by normal human monocytes. 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-1 beta message and transcriptional rate of the pro-IL-1 beta gene in human monocytes after 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 h after 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 to 3 h lag period may be necessary for production of a protein(s) that 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) that mediates these effects.
Donnelly
R P
RP
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
Fenton
M J
MJ
Kaufman
J D
JD
Gerrard
T L
TL
D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D015847:Interleukin-4; D003513:Cycloheximide