NORMAL AND PATHOLOGIC MECHANISMS OF INFLAMMATION AND REPAIR

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Evolution of inflammatory and immune reactions is dependent upon the recruitment, migration and activation of circulating leukocytes at a site of injury or antigen deposition. Long range goals of this laboratory foucs on characterizing and modulating these events. By suppressing monocyte functions and promoting the expression of an IL-1 receptor antagonist (IL-1ra) that blocks the action f IL-1 by speicifically binding to the IL-1 receptor without initiating signal transduction, IL-4 may contribute to the down-regulation and resolution of an inflammatory response. In vitro analysis of IL-4 regulation of monocyte phenotype and function revealed a dose-dependent induction of IL-1ra mRNA within 2 to 4 hours without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. Peripheral blood monocytes from cancer patients, obtained prior to and immediately after a regimen of IL-4 immunotherapy, were also examined for IL-1ra gene expression. After IL-4 treatment, monocytes from the patients showed a marked increase in the expression of IL-1ra mRNA. This induction of IL-1ra in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (P<0.05) during IL-4 therapy which subsequently declined. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we have demonstrated both in vitro and in vivo, suggest that IL-4 may prove clinically useful as an anti-inflammatory agent.