ACTIVATION OF INTERLEUKIN-1β-CONVERTING ENZYME BY NIGERICIN IS INDEPENDENT OF APOPTOSIS

Abstract

Interleukin-1β-converting enzyme (ICE) is believed to be one of the key proteases involved in apoptosis. Since the precursor form of interleukin-1β (pre-IL-1β) is one of the well known substrates for ICE, and a potassium/proton ionophore, nigericin, enhances IL-1β processing, the authors hypothesized that nigericin induces apoptosis through the activation of ICE. In a lipopolysaccharide (LPS)-stimulated and nigericin-treated human monocytic cell line, THP-1, apoptosis was induced, as assessed as to a decrease in cell size, chromatin condensation, exposure of phosphatidylserine and DNA fragmentation. Under exactly the same conditions, nigericin also induced IL-1β processing in these cells, which was significantly inhibited by an ICE inhibitor, acetyl-Tyr-Val-Ala-Asp-CHO. On the contrary, treatment with this inhibitor at the same concentration did not inhibit nigericin-induced apoptosis, assessed as to the decrease in cell size, chromatin condensation and DNA fragmentation. Although apoptosis induced by nigericin was also observed for LPS-stimulated human peripheral blood mononuclear cells and a mouse T lymphoma cell line, EL-4, the ICE inhibitor did not inhibit the apoptosis in the cells. These results suggest that activated ICE is not involved in the apoptosis induced by nigericin. Since apopain activity was not augmented under the same conditions, neither ICE nor apopain may play any role in the nigericin-induced apoptosis.