Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta-converting enzyme-mediated apoptosis.
Prointerleukin-1 beta (pro-IL-1 beta) is the only known physiologic substrate of the interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), the founding member of the ICE/ced-3 cell death gene family. Since secreted mature IL-1 beta 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 alpha in fibroblasts. In addition, during the G1/S phase arrest, mature IL-1 beta 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-1 beta for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1 beta 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-1 receptor. Our findings demonstrate that pro-IL-1 beta is a substrate of ICE relevant to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1 beta may function as a positive or negative mediator of cell death.
Friedlander
R M
RM
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown 02129, USA.
Gagliardini
V
V
Rotello
R J
RJ
Yuan
J
J
D000818:Animals; D017209:Apoptosis; D020170:Caspase 1; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D007375:Interleukin-1 / Q000502:physiology*; D007739:L Cells; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D003546:Cysteine Endopeptidases; D020170:Caspase 1