Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells.
We investigated effects of corticosteroids on interleukin 1 (IL-1) production in monocyte-like tumor cell line, U937. Release of IL-1 activity by bacterial toxin-stimulated cells was completely blocked by 10 nM dexamethasone (Dex). We examined the question whether corticosteroids suppress IL-1 production by blocking transcription of IL-1 mRNA, or by blocking IL-1 synthesis at a post-transcriptional step. Northern blot hybridization analysis indicated that Dex, 10 nM, completely blocked accumulation of IL-1 beta-encoding mRNA in U937 cells. Dex-mediated inhibition of IL-1 release appeared to be glucocorticoid receptor-mediated and was abrogated by progesterone. In addition, Dex at high concentrations could inhibit post-transcriptional synthesis of IL-1 by prestimulated U937 cells. Although Dex, 500 nM, did not change IL-1 mRNA levels in prestimulated cells, it completely blocked IL-1 release and induced a transient increase in cellular cyclic adenosine 3',5'-monophosphate (cAMP) levels. Dex-mediated inhibition of IL-1 release in prestimulated cells is likely to occur via increased levels of cAMP, which have been shown to block post-transcriptional IL-1 synthesis. Our results indicate that glucocorticoids suppress IL-1 synthesis by two distinct mechanisms, blocking transcription of IL-1 mRNA during monocyte activation, and blocking post-transcriptional IL-1 synthesis via cAMP.
Knudsen
P J
PJ
Charles A. Dana Research Institute, Boston, MA.
Dinarello
C A
CA
Strom
T B
TB
D000450:Aldosterone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D007375:Interleukin-1; D012333:RNA, Messenger; D000450:Aldosterone; D003907:Dexamethasone; D000242:Cyclic AMP