Functional role of interleukin 1β (IL-1β) in IL-1β-converting enzyme- mediated apoptosis

Abstract

Prointerleukin-1β (pro-IL-1β) is the only known physiologic substrate of the interleukin-1β (IL-1β)-converting enzyme (ICE), the founding member of the ICE/ced-3 cell death gene family. Since secreted mature IL-β has been detected after apoptosis, we investigated whether this cytokine, when produced endogenously, plays a role in cell death. We found that hypoxia- induced apoptosis can be inhibited by either the IL-1 receptor antagonist (IL-1Ra) or by neutralizing antibodies to IL-1 or to its type 1 receptor, IL- 1Ra also inhibits apoptosis induced by trophic factor deprivation in primary neurons, as well as by tumor necrosis factor α in fibroblasts. In addition, during the G1/S phase arrest, mature IL-1β induces apoptosis through a pathway independent of CrmA-sensitive gene activity. We also demonstrate that ICE, when expressed in COS cells, requires the coexpression of pro-IL-1β for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1β has antiapoptotic activity when added exogenously before the onset of hypoxia, which we found is caused in part by its ability to downregulate the IL-1β receptor. Our findings demonstrate that pro-IL- 1β is a substrate of ICE relevant to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1β may function and a positive or negative mediator of cell death.