REGULATION OF CYTOKINE PRODUCTION BY IL-10 IN ENDOTOXIN-STIMULATED MONOCYTES

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Stimulation of human monocytes with bacterial endotoxin, lipopolysaccharide (LPS), induces expression of multiple cytokines, including TNF-a, IL-1b, IL-6 and IL-10. IL-10 expression is delayed relative to that of TNF-a, IL-1b and IL-6. Furthermore, IL-10 feedback inhibits expression of TNF-a, IL-1b and IL-6, thus providing an efficient autocrine mechanism for controlling proinflammatory cytokine production in monocytes. The Th1-type lymphokine, IFN-g, markedly upregulates TNF-a production in monocytes. However, the precise mechanism by which IFN-g mediates this effect is unknown. We examined the effects of IFN-g on IL-10 expression in LPS-stimulated monocytes, and the relationship between IL-10 and TNF-a production in these cells. LPS stimulation induced rapid, ordered expression of multiple cytokines. Steady-state mRNA levels for TNF-a increased rapidly, reached maximal levels by 2-3 hr post stimulation, and then declined sharply. IL-1b and IL-6 mRNA levels also increased markedly following stimulation with LPS, but decreased more slowly than TNF-a. Downregulation of mRNA for TNF-a, IL-1b and IL-6 coincided with a delayed and more gradual increase in IL-10 mRNA levels. Furthermore, neutralization of IL-10 with anti-IL-10 antibodies prolonged TNF-a mRNA expression, and significantly increased net TNF-a production. IFN-g suppressed expression of IL-10 mRNA and protein in a dose-dependent manner. Moreover, inhibition of IL-10 production correlated with a marked increase in both the magnitude and duration of TNF-a expression. Thus, potentiation of TNF-a production by IFN-g in monocytes is coupled to inhibition of endogenous IL-10 expression. These findings were recently documented in a paper in the Journal of Immunology (Donnelly et al. 1995. J. Immunol. 155:1420-1427). In future experiments, we will attempt to define the mechanism by which IL-10 downregulates cytokine production, particularly TNF-a, in activated monocytes. In this context, we will also examine the tissue specificity of this IL-10-induced effect. In preliminary experiments, we have found that although IL-10 markedly inhibits production of TNF-a in monocytes, it does not inhibit expression of TNF-a in activated CD3+ T cells. Thus, the inhibitory action of IL-10 may be inducible in monocytic but not lymphocytic cells. The results of these and related studies will enhance our knowledge of the biological actions of IL-10, and thereby improve our ability to regulate this cytokine as a potential therapeutic agent for the treatment of certain inflammatory diseases.