Rm. Friedlander et al., FUNCTIONAL-ROLE OF INTERLEUKIN-1-BETA (IL-1-BETA) IN IL-1-BETA-CONVERTING ENZYME-MEDIATED APOPTOSIS, The Journal of experimental medicine, 184(2), 1996, pp. 717-724
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.