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  • Title: Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes.
    Author: Granowitz EV, Clark BD, Vannier E, Callahan MV, Dinarello CA.
    Journal: Blood; 1992 May 01; 79(9):2356-63. PubMed ID: 1533322.
    Abstract:
    Interleukin-1 (IL-1) induces IL-1, tumor necrosis factor alpha (TNF alpha), and IL-6 gene expression and synthesis in a variety of cells. In this study, we investigated the ability of human recombinant IL-1 receptor antagonist (IL-1ra) to inhibit IL-1-induced cytokine production in human peripheral blood mononuclear cells (PBMC) and isolated monocytes. IL-1ra alone at concentrations as high as 1 microgram/mL did not induce IL-1 alpha, IL-1 beta, TNF alpha, or IL-6 synthesis. Suppression of IL-1-induced IL-1, TNF alpha, or IL-6 synthesis was dose-dependent (P less than or equal to .0001). At a twofold molar excess, IL-1ra inhibited IL-1-induced IL-1 or TNF alpha synthesis by 50% (P less than .01); an equimolar concentration of IL-1ra inhibited synthesis of these two cytokines by over 20% (P less than .05). A 10-fold molar excess of IL-1ra over IL-1 beta reduced IL-1 beta-induced IL-1 alpha by 95% (P = .01) and IL-1 alpha-induced IL-1 beta by 73% (P less than .01). IL-1ra added to PBMC 8 hours after stimulation with IL-1 beta was still able to inhibit IL-1 alpha, TNF alpha, and IL-6 synthesis (P less than or equal to .01). A similar reduction in IL-1 beta-induced IL-1 alpha was observed when IL-1 beta was removed from the cultures after 8 hours of stimulation (P less than .05), suggesting a prolonged presence of IL-1 or restimulation of IL-1 receptors on monocytes is required for the induction of cytokines. In elutriated monocytes, a 10-fold molar excess of IL-1ra reduced IL-1 beta-induced IL-1 alpha by 82% (P less than .05), TNF alpha by 64% (P = .05), and IL-6 by 47% (P less than .05). 125I-IL-1 beta was bound to purified monocytes, cross-linked, and immunoprecipitated. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a band at 85 Kd corresponding to the 68-Kd IL-1 receptor type II (IL-1RtII). Excess unlabeled IL-1 beta or IL-1ra blocked the binding of 125I-IL-1 beta to the IL-1RtII. We conclude that IL-1ra inhibits IL-1-induced cytokine synthesis and competes with IL-1 for the IL-1RtII on human monocytes.
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