Glucocorticoids suppress interleukin-1 receptor antagonist synthesis following induction by endotoxin.
Glucocorticoids, as part of their physiological role in the control of inflammatory and immune processes, suppress the expression of IL-1 and other cytokines. We have found a dose-dependent inhibition by dexamethasone (10 nM to 10 microM) of mRNA levels of the recently cloned IL-1 receptor antagonist (IL-1ra) in endotoxin-stimulated human monocytes. At the same concentrations, both dexamethasone and cortisol inhibited the secretion of IL-1ra. These inhibitory effects were reversed by blocking glucocorticoid receptors with the specific antagonist RU 38486, but not by adding exogenous IL-1, even up to 100 ng/ml, to the monocytes. A similar inhibition of IL-1ra mRNA and protein secretion was found in monocytes obtained after dexamethasone administration in vivo. In addition, we observed parallel increases in glucocorticoid and IL-1ra levels following endotoxin administration to normal volunteers. Our results show that glucocorticoids shut down not only IL-1 but also IL-1ra expression, ruling out induction of IL-1ra as part of the glucocorticoid antiinflammatory mechanism. The control of the delicate immunoregulatory balance of the IL-1/IL-1ra system during endotoxemia underscores the physiological importance of glucocorticoids in the final control of immune responses.
Arzt
E
E
Max-Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
Sauer
J
J
Pollmächer
T
T
Labeur
M
M
Holsboer
F
F
Reul
J M
JM
Stalla
G K
GK
D000328:Adult; D015152:Blotting, Northern; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000097:blood
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D015735:Mifepristone; D003907:Dexamethasone; D006854:Hydrocortisone