The urine of febrile humans contains a 30- to 35-Kda glycoprotein (febrile inhibitor) that inhibits interleukin 1 (IL-1)-induced proliferation of murine thymocytes. In the present investigation, the mechanism of action of this febrile inhibitor was analyzed. The inhibitor was not cytotoxic for thymocytes and it did not act by inhibiting the uptake or incorporation of [3H]TdR. The effects of the inhibitor were not blocked by indomethacin, suggesting that it was not acting by a prostaglandin-mediated pathway. The inhibitor appeared to be acting at a later stage of the cell activation sequence, since it was still effective when added as late as 48 hr after the addition of IL-1. However, it did not block the ability IL-1 to bind and activate thymocytes but did block the proliferation of IL-1-primed cells. The inhibitor did not suppress the activation of thymocytes induced by concanavalin A, but did block the augmentation of this response by IL-1. These results suggest that the target of the febrile inhibitor is on IL-1-primed thymocytes, and that it acts at a stage after the initial activation of the cell by IL-1.
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