Dexamethasone suppresses release of soluble TNF receptors by human monocytes concurrently with TNF-alpha suppression.
Glucocorticoids suppress many monocyte functions, including endotoxin-stimulated release of TNF-alpha. Monocytes also release soluble receptors for TNF (sTNF-R), which can modulate TNF bioactivity. We therefore examined the effects of the glucocorticoid, dexamethasone, on the release of soluble forms of the 55 kDa and 75 kDa receptors for TNF (sTNF-R55 and sTNF-R75) by human monocytes and the human monocytic Mono Mac 6 cell line. Peripheral blood mononuclear cells (PBMC) spontaneously released 406 +/- 181 pg/10(6) cells of sTNF-R75 over 18 h in culture and Mono Mac 6 cells released 554 +/- 29 pg/10(6) cells. Lipopolysaccharide (LPS) exposure increased release of sTNF-R75 by 54 and 217%, respectively. Dexamethasone suppressed both spontaneous and LPS-stimulated release. The effect of dexamethasone was concentration dependent. At 1 mumol/L, dexamethasone suppressed the LPS-stimulated release of sTNF-R75 by 86% in PBMC and by 40% in Mono Mac 6 cells. Neither PBMC nor Mono Mac 6 cells released measurable amounts of sTNF-R55, but spontaneous release of sTNF-R55 from purified human monocytes (55 +/- 2 pg/10(6) cells over 18 h) was reduced by 45% in the presence of dexamethasone. Dexamethasone reduced bioactive TNF in PBMC cultures, as well as immunoassayable TNF-alpha, which indicates that suppression of TNF-alpha release was biologically more important than suppressed release of soluble inhibitors. Similar concurrent suppression of IL-1 beta and IL-1ra release occurred in PBMC and Mono Mac 6 cultures exposed to dexamethasone.
Joyce
D A
DA
Department of Pharmacology, University of Western Australia, Nedlands, Australia. djoyce@receptor.pharm.uwa.edu.au
Kloda
A
A
Steer
J H
JH
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone