THE IL-1-BETA-CONVERTING ENZYME (CASPASE-1) INHIBITS APOPTOSIS OF INFLAMMATORY NEUTROPHILS THROUGH ACTIVATION OF IL-1-BETA

IL-1 beta-converting enzyme (ICE), also known as caspase-1, subserves two dichotomous biologic roles. It processes newly synthesized pro-IL- 1 beta to yield the active cytokine and, as the human homologue of the Caenorhabditis elegans gene product, ced-3, it also induces cellular apoptosis through the cleavage of key intracellular structural and reg ulatory proteins and through the catalytic activation of other caspase family members. We show here that two different proinflammatory stimu li, LIPS and granulocyte-macrophage-CSF, up-regulate the expression of both ICE and IL-1 beta in human polymorphonuclear neutrophils, and th at the ICE-dependent cleavage of pro-IL-1 beta results in delayed expr ession of the constitutive cell death program. The apoptotic delay can be blocked by inhibiting tyrosine kinases or NF-kappa B activation an d by inhibiting protein synthesis. Since an antisense oligonucleotide for IL-1 beta, a blocking Ab to IL-1 beta, and preincubation with the IL-1R antagonist all prevent the delay in apoptosis, we conclude that IL-1 beta acts in an autocrine manner to inhibit granulocyte programme d cell death. We conclude that caspase-1 (ICE) subserves both pro- and antiapoptotic roles; the latter role is evident during inflammation a s an inhibition of spontaneous neutrophil apoptosis through the proces sing of IL-1 beta. The ICE-dependent activation of IL-1 beta may repre sent a common autocrine pathway for the divergent stimuli that inhibit the constitutive expression of neutrophil programmed cell death durin g inflammation.