Augmentation of IL 1-induced fibroblast PGE2 production by a urine-derived IL 1 inhibitor.

IL 1, a monocyte-derived cytokine, has potent biologic effects in a variety of target tissues. The existence of naturally occurring inhibitors of IL 1 activity has been recently described; these inhibitors blocked one IL 1 effect: stimulation of thymocyte responses to mitogens. We examined the effect of one well-characterized inhibitor of IL 1, isolated from the urine of febrile patients, on a second IL 1 effect, stimulation of fibroblast PGE synthesis. In this system, purified preparations of the urinary inhibitor that completely blocked murine thymocyte proliferative responses to mitogen failed to block PGE synthetic responses to IL 1. Rather, inhibitor preparations markedly enhanced fibroblast PGE synthetic responses to IL 1. When partially purified inhibitor preparations were fractionated by ion exchange chromatography, inhibitory activity for the IL 1 effect on thymocytes and PGE stimulatory activity co-eluted. Augmentation of the IL 1-induced PGE response was seen with both low (1:1 unit) and high (400:1) ratios of inhibitor to IL 1. Inhibitor preparations alone did not stimulate fibroblast PGE synthesis. The augmentation of fibroblast PGE synthesis by inhibitor preparations was not due to contaminating endotoxin. Active inhibitor preparations contained less than 15 pg of endotoxin/U activity, and the PGE stimulatory effect was not blocked by the addition of polymyxin B, whereas polymyxin B reversed the effects of exogenous endotoxin. It appears that the inhibition of IL 1 effects by naturally occurring inhibitors may have target cell and/or functional specificity.