REGULATION OF IL-1 AND IL-1 RECEPTOR ANTAGONIST EXPRESSION BY IL-4

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In this project, we evaluated the effects of the T cell-derived lymphokine IL-4, on the ability of human monocytes to express IL-1 and the IL-1 receptor antagonist (IL-lra), a new member of the IL-1 gene family. Activation of human monocytes with lipopolysaccharide (LPS) induces coordinate expression of a number of proinflammatory cytokine genes, including IL-lalpha, IL-1beta, TNF-alpha, IL-6 and IL-8. IL-4 inhibits expression of these genes in monocytes, suggesting that it may be an important physiologic regulator of cytokine production. We have previously shown that IL-4 reduces steady-state mRNA levels for IL-lbeta in human monocytes by decreasing both IL-lbeta transcription and the half -life of newly formed IL-lbeta mRNA transcripts. We have now extended these findings to show that IL-4 similarly accelerates the turnover of IL-6 mRNA in LPS-stimulated monocytes. However, this inhibition of cytokine expression and dramatic increase in the decay rate of cytokine mRNA does not extend to all LPS-inducible genes because IL-4 treatment did not inhibit expression or accelerate turnover of mRNA for IL-lra in the same cells. Although IL-lbeta and IL-lra are both LPS-inducible genes, they displayed distinct temporal patterns of expression. Peak steady-state mRNA levels for IL-lra lagged significantly behind that of IL-1beta, suggesting a possible endogenous mechanism for limiting IL-1 biologic activity. Furthermore, although IL-4 suppressed expression of both IL-1beta and IL-6, it upregulated synthesis of IL-lra mRNA and protein. Thus, IL-4 inhibits production of the proinflammatory cytokine IL-1beta while increasing synthesis of IL-lra in activated human monocytes. This pathway may have evolved to provide a mechanism by which the host can effectively regulate both the production and activity of this potent proinflammatory mediator. Furthermore, these findings provide additional support for the potential therapeutic use of IL-4 in disease states which are characterized by excessive production of IL-1.