A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes

Abstract

Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.

An ICE‐like protease is a common mediator of apoptosis induced by diverse stimuli in human monocytic THP.1 cells

“…Our data demonstrating that Z-VAD.FMK but not YVAD.CHO and YVAD.CMK inhibited apoptosis may have been due to a differential cell permeability of the inhibitors or to the possible involvement of an ICE homologue(s) other than ICE as a common mediator of apoptosis. This is based on the observations of the absolute requirement of peptide substrates of ICE for an aspartate in the P1 position and also that they must contain at least four amino acids on the N-terminal side of the cleavage site, as removal of the amino acid in the P4 position results in a very marked loss of activity [25]. Thus Z-VAD.FMK, with an aspartate in the P1 position but no amino acid in the P4 position, should inhibit ICE-like proteases but not ICE per se.…”

“…Much interest has focussed on ICE due to its structural similarity to ced-3 [8]. ICE, identified and isolated from human monocytic THE 1 cells, cleaves prolL-lfl between Asp ~ 16 and Ala ~7 to yield the active 17.5 kDa cytokine [25]. This protease has an unusual requirement for aspartic acid in the P1 position, a property possessed by only one other known protease, granzyme B [26].…”

“…In contrast, TLCK inhibits trypsin-like proteases, which require a basic amino acid in the P1 position [27]. Peptide substrates for ICE must also contain at least four amino acids in the P1-P4 positions [25]. A critical role in apoptosis for an ICE homologue(s) rather than ICE per se was suggested by the finding that thymocytes and macrophages from ICE-deficient mice undergo apoptosis normally [28], although it is not possible to exclude redundancy in the system.…”

The estrogen-responsive B box protein: a novel enhancer of interleukin-1β secretion

“…[3][4][5] Processing and activation of proIL-1b is strictly dependent on the protease caspase-1, which cleaves proIL-1b after the aspartic acid residue at position 116, generating active IL-1b. 6,7 Consequently, macrophages from caspase-1 knockout mice cannot produce mature IL-1b. 8 Caspase-1 itself is expressed as an inactive precursor.…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…This is well known for both interlukin (IL)-1 and TNF, proteolytically activated by the IL1-converting enzyme (ICE, better known as caspase 1; Thornberry et al, 1992) and the TNF-converting enzyme (TACE, or ADAM17; Moss et al, 1997), respectively. Provided that IL-1 is not the most relevant cytokine in the pathogenesis of cachexia, most of the studies have concentrated on the search for inhibitors to TACE, in order to prevent dangerous increases of TNF levels.…”