Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability.
The mechanism by which glucocorticoids inhibit interleukin (IL)-1 and IL-6 formation in human monocytes and a promonocytic cell line activated by Escherichia coli lipopolysaccharide was analyzed. Dexamethasone (DEX) decreased levels of IL-1 alpha and IL-1 beta mRNAs in a dose-related fashion. The DEX-induced decrease in levels of IL-1 alpha and IL-1 beta mRNAs was abolished by the steroid receptor antagonist RU486. The levels of IL-1 alpha and IL-1 beta proteins within the cells and of IL-1 beta in the culture medium were decreased by DEX to comparable extents, so that DEX had no detectable effect on cytokine secretion. DEX did not influence lipopolysaccharide-induced transcription of the IL-1 beta gene in monocytes. However, DEX markedly decreased the stability of IL-1 beta mRNA, as shown both by steady state measurements and by pulse-labeling. DEX-induced instability of IL-1 beta mRNA required protein synthesis. DEX was also found to be a potent inhibitor of IL-1-induced expression of the IL-6 gene in connective tissue-type cells from the synovium of patients with rheumatoid arthritis. Inhibition of the formation of proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha, is a mechanism by which glucocorticoids exert anti-inflammatory effects. Inhibition by glucocorticoids of the expression of IL-1 alpha in antigen-presenting cells could decrease the capacity of the cells to stimulate the proliferation of T lymphocytes. This activity, as well as inhibition of the production and effects of IL-1 beta, including induced formation of IL-6 and of certain lymphokines, could explain the immunosuppressive effects of glucocorticoids.
Amano
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Y
Syntex Research, Palo Alto, California 94304.
Lee
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SW
Allison
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AC
D002460:Cell Line; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D015735:Mifepristone; D003907:Dexamethasone