Structure and mechanism of interleukin-lβ converting enzyme

Wilson, Keith; Black, James; Thomson, John A.; Kim, E.E; Griffith, Jeffrey K.; Navia, Manuel A.; Murcko, Mark A.; Chambers, Stephen P.; Aldape, Robert A.; Raybuck, Scott A.

doi:10.1038/370270a0

Cited by 817 publications

(631 citation statements)

References 37 publications

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“…In conclusion, we found that IL-6 was has been shown to be a useful strategy for inhibiting induced by IFN-a in vivo, and that this induction was the production of circulating TNF-a 11,12 and IL-1b. 13,14 completely abrogated by the administration of GM. Our In a previous study, we found that gabexate mesilate results indicate that serine protease inhibitors may be (GM), a serine protease inhibitor, suppressed the elevauseful for inhibiting IL-6-relating responses.…”

mentioning

confidence: 93%

Induction of interleukin-6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C

et al. 1996

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We investigated short-term alterations in plasma in-rently used in the treatments of chronic hepatitis B 3,4 terleukin-6 (IL-6), interleukin-1b (IL-1b), and tumor ne-and C 5,6 and for the treatment of some malignant tucrosis factor a (TNF-a) levels induced by interferon alfa mors. 7 (IFN-a) injection in 18 patients with chronic hepatitis C. IFN-a induces various biological responses, such asA single intramuscular injection of human recombinant fever and general malaise. Whereas some of these re-IFN-a 2a (6 million units [MU]) significantly increased sponses could be caused by the direct effects of IFN-a the plasma IL-6 level 6 hours after the injection (P itself, others may be attributed to the effects of cytokine õ .05). On the other hand, the IFN-a injection did not interactions. Interleukin-6 (IL-6), interleukin-1b (ILaffect the plasma TNF-a and IL-1b levels. Polymerase 1b), and tumor necrosis factor a (TNF-a) are multifuncchain reaction (PCR) analysis showed accumulation of tional cytokines that are induced in inflammatory re-IL-6 gene transcripts in peripheral blood mononuclear cells (PBMC) after IFN-a injection, indicating that IFN-sponses. 8 However, little is known about the in vivo a enhances IL-6 production at the messenger RNA level. modulation of these cytokines by IFN-a. IFN-a therapy The induction of IL-6 by IFN-a was completely sup-for chronic hepatitis C is a good model in which to study pressed by the intravenous administration of gabexate these cytokine interactions. In this study, we examined mesilate (GM), a serine protease inhibitor. The mecha-the short-term effects of IFN-a on IL-6, IL-1b, and nism whereby GM suppresses the elevation in circulat-TNF-a in patients with chronic hepatitis C.ing IL-6 levels seems to be the inhibition of IL-6 producCurrent interests in cytokine research are now being tion at the messenger RNA level. Elevations of both directed to the modulation of circulating cytokines, and serum C-reactive protein (CRP) levels and body tempersuppression of the excess production of cytokines in ature after GM-suppressed IFN-a injection suggest that various human pathophysiological conditions is now the administration of GM, by suppressing IL-6 production, may attenuate the IL-6-related responses induced under investigation. 9,10 The use of protease inhibitors by IFN-a injection. In conclusion, we found that IL-6 was has been shown to be a useful strategy for inhibiting induced by IFN-a in vivo, and that this induction was the production of circulating TNF-a 11,12 and IL-1b. 13,14 completely abrogated by the administration of GM. Our In a previous study, we found that gabexate mesilate results indicate that serine protease inhibitors may be (GM), a serine protease inhibitor, suppressed the elevauseful for inhibiting IL-6-relating responses. (HEPATOL-tion of serum IL-6 levels after transcatheter arterial OGY 1996;23:669-675.) embolization for the treatment of hepatocellular carcinoma. 15 Our observations suggested that GM is a poInterferon (IFN) is recognized as a potent antiv...

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confidence: 93%

Induction of interleukin-6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C

et al. 1996

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“…The active enzyme is a tetramer of two p20 subunits surrounding two adjacent p10 subunits, with most of the area of contact between the dimers occurring between the p10 subunits [40,41]. Interactions between the p20 C-terminus and the p10 N-terminus also contribute to the stability of the homodimer.…”

Section: Structure and Functionmentioning

confidence: 99%

Caspases: the executioners of apoptosis

Cohen

1997

Biochemical Journal

4,306

2,952

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Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1β-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P " position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide activesite motif. Caspases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) poly-

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“…Crystal structures of caspase-1 (ICE) (Walker et al, 1994;Wilson et al, 1994) and caspase-3 (CPP32/Yama/apopain) (Rotonda et al, 1996) suggest that active forms of caspases are tetramers composed of two pairs of large and small subunits, which are derived from two molecules of a precursor by cleavage at multiple Asp-X bonds. This unusual proteolytic processing suggests that caspase activation is driven by autocatalysis, or by cleavage by other caspases (Martin and Green, 1995).…”

Section: Introductionmentioning

confidence: 99%

Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmA-sensitive caspase-8

et al. 1997

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The activation of multiple interleukin-1b converting enzyme-related proteases (caspases) in apoptotic mammalian cells raises questions as to whether the multiple active caspases have distinct roles in apoptotic execution as well as how these proteases are organized in apoptotic signaling pathways. Here we used an a nity-labeling agent, YV(bio)KD-aomk, to investigate the caspases activated during apoptotic cell death. YV(bio)KD-aomk identi®ed six distinct polypeptides corresponding to active caspases in Fas-stimulated Jurkat T cells. On staurosporine treatment, four polypeptides were detected. Competition experiments showed that the labeled caspases have distinct substrate preferences. Stepwise appearance of the labeled caspases in each cell death event was consistent with the view that the activated caspases are organized into protease cascades. Moreover, we found that stepwise activation of caspases similar to that induced by Fas ligation is triggered by exposing non-apoptotic Jurkat cell extracts to caspase-8 (MACH/FLICE/Mch5). Conversely, CrmA protein, a viral suppressor of Fas-induced apoptosis, inhibited the protease activity of caspase-8. Overall, these ®ndings provide evidence that caspase-8, a CrmA-sensitive protease, is responsible for initiating the stepwise activation of multiple caspases in Fas-stimulated cells.

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Structure and mechanism of interleukin-lβ converting enzyme

Cited by 817 publications

References 37 publications

Induction of interleukin-6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C

Induction of interleukin-6 by interferon alfa and its abrogation by a serine protease inhibitor in patients with chronic hepatitis C

Caspases: the executioners of apoptosis

Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmA-sensitive caspase-8

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