MACROPHAGE APOPTOSIS IN THE ABSENCE OF ACTIVE INTERLEUKIN-1-BETA-CONVERTING ENZYME

The interleukin-1 beta converting enzyme (ICE) is the cysteine protein ase responsible for cleaving the 31-kDa interleukin-1 beta (IL-1 beta) precursor to its active 17-kD a form. In lipopolysaecharide-stimulate d cultured macrophages, induction of apoptosis but not necrosis effect ively induces conversion of the IL-1 beta precursor to its mature form and results in the concomitant release of the mature cytokine from th e cell. To determine whether ICE activity is required for macrophage a poptosis, we have exposed macrophages either to 5 mM ATP or to allorea ctive cytolytic T lymphocytes (CTL) in the absence and presence of the ICE inhibitor peptide YVAD-chloromethylketone (YVAD-cmk). Activated c ells treated with YVAD-cmk and ATP or CTL showed no mature IL-1 beta i n either the cell lysates or the culture supernatants, indicating effe ctive inhibition of ICE activity; however, the YVAD-treated macrophage s showed no detectable change in Cr-51 release or nuclear fragmentatio n, indicating failure to inhibit apoptotic cell death. Thus, in these cells, YVAD-cmk uncouples IL-1 beta processing and apoptosis.