FUNCTIONAL-ROLE OF INTERLEUKIN-1-BETA (IL-1-BETA) IN IL-1-BETA-CONVERTING ENZYME-MEDIATED APOPTOSIS

Prointerleukin-1 beta (pro-IL-1B) is the only Known physiologic substr ate of the interleukin-1B (IL-1 beta)-converting enzyme (ICE), the fou nding member of the ICE/ced-3 cell death gene family. Since secreted m ature IL-1 beta has been detected after apoptosis, we investigated whe ther this cytokine, when produced endogenously, plays a role in cell d eath. We found that hypoxia-induced apoptosis car, be inhibited by eit her the IL-1 receptor antagonist (IL-1Ra) or by neutralizing antibodie s to IL-1 or to its type 1 receptor. IL-1Ra also inhibits apoptosis in duced by trophic factor deprivation in primary neurons, as well as by tumor necrosis factor alpha in fibroblasts. In addition, during the G( 1)/S phase arrest, mature IL-1 beta induces apoptosis through a pathwa y independent of CmA-sensitive gene activity. We also demonstrate that Ice, when expressed in COS cells, requires the coexpression of pro-IL -1 beta for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1 beta has antiapoptotic activi ty when added exogenously before the onset of hypoxia, which we round is caused in part by its ability to downregulate the IL-1 receptor. Ou r findings demonstrate that pro-IL-1 beta is a substrate of ICE releva nt to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1 beta may function as a positive or negative me diator of cell death.