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Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II. IL-1
receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis
by human monocytes
EV Granowitz, E Vannier, DD Poutsiaka and CA Dinarello
Department of Medicine, New England Medical Center Hospitals, Boston, MA.
Lipopolysaccharide (LPS) stimulates interleukin-1 (IL-1) and tumor necrosis
factor alpha (TNF alpha) gene expression and synthesis in human peripheral
blood mononuclear cells (PBMC). IL-1 can also induce PBMC to synthesize
IL-1 and TNF alpha. In the present study, we used IL- 1 receptor antagonist
(IL-1ra) to determine the relative contribution of an IL-1-positive
feedback loop to the total amount of LPS-induced cytokine synthesis.
Pretreatment of PBMC with human recombinant IL-1ra reduced LPS-induced
cytokine synthesis in a dose-dependent manner (P less than .001). Maximal
inhibition was 33% for IL-1 alpha (P less than .01), 43% for IL-1 beta (P =
.001), and 20% for TNF alpha (P less than .05). We consistently observed
IL-1ra suppression of LPS-induced cytokines in PBMC of 38 volunteers.
However, this phenomenon was not specific for LPS; 1 microgram/mL IL-1ra
inhibited IL-1 beta synthesized in response to human recombinant IL-2 by
44% (P less than .001), toxic shock syndrome toxin-1 by 26% (P less than
.05), and phorbol 12- myristate 13-acetate by 76% (P less than .001).
IL-1ra added to PBMC 4 or 8 hours after stimulation with LPS still
inhibited IL-1 beta synthesis by 44% (P less than .001) or 25% (P = .01),
respectively. The steady state messenger RNA levels of IL-1 beta were
reduced in PBMC stimulated by LPS in the presence of IL-1ra. In monocytes
isolated by elutriation, IL-1ra reduced LPS-induced IL-1 alpha by 16% (P
less than .001), IL-1 beta by 14% (P less than .05), and TNF alpha by 24%
(P = .01). We conclude that IL-1-induced IL-1 significantly contributes to
LPS-induced cytokine synthesis.
Volume 79,
Issue 9,
pp. 2364-2369,
05/01/1992
Copyright © 1992 by The American Society of Hematology
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