The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages.

ABSTRACT The invasive enteropathogenic bacterium Shigella flexneri activates apoptosis in macrophages.Shigella-induced apoptosis requires caspase-1. We demonstrate here that tripeptidyl peptidase II (TPPII), a cytoplasmic, high-molecular-weight protease, participates in the apoptotic pathway triggered by Shigella. The TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) andclasto-lactacystin β-lactone (lactacystin), an inhibitor of both TPPII and the proteasome, protected macrophages fromShigella-induced apoptosis. AAF-cmk was more potent than lactacystin and irreversibly blocked Shigella-induced apoptosis by 95% at a concentration of 1 μM. Conversely, peptide aldehyde and peptide vinylsulfone proteasome inhibitors had little effect on Shigella-mediated cytotoxicity. Both AAF-cmk and lactacystin prevented the maturation of pro-caspase-1 and its substrate pro-interleukin 1β in Shigella-infected macrophages, indicating that TPPII is upstream of caspase-1. Neither of these compounds directly inhibited caspase-1. AAF-cmk and lactacystin did not impair macrophage phagocytosis or the ability of Shigellato escape the macrophage phagosome. TPPII was also found to be involved in apoptosis induced by ATP and the protein kinase inhibitor staurosporine. We propose that TPPII participates in apoptotic pathways.

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Expression of a Dominant Negative Mutant of Interleukin-1β Converting Enzyme in Transgenic Mice Prevents Neuronal Cell Death Induced by Trophic Factor Withdrawal and Ischemic Brain Injury

Journal of Experimental Medicine ◽

10.1084/jem.185.5.933 ◽

1997 ◽

Vol 185 (5) ◽

pp. 933-940 ◽

Cited By ~ 256

Author(s):

Robert M. Friedlander ◽

Valeria Gagliardini ◽

Hideaki Hara ◽

Klaus B. Fink ◽

Weiwei Li ◽

...

Keyword(s):

Brain Injury ◽

Transgenic Mice ◽

Dorsal Root ◽

Neuron Specific Enolase ◽

Dominant Negative ◽

Trophic Factor ◽

Dominant Negative Mutant ◽

Lacz Gene ◽

Converting Enzyme ◽

Induced Apoptosis

To explore the role of the interleukin (IL)-1β converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal–induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro–IL-1β, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal–induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal–induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1β convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1β production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.

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Distinct interleukin-1β-converting enzyme family proteases mediate cisplatin- and staurosporine-induced apoptosis of mouse proximal tubule cells

Life Sciences ◽

10.1016/s0024-3205(98)00036-8 ◽

1998 ◽

Vol 62 (12) ◽

pp. 1125-1138 ◽

Cited By ~ 21

Author(s):

Kazuhito Fukuoka ◽

Michio Takeda ◽

Mami Kobayashi ◽

Takako Osaki ◽

Isao Shiratc ◽

...

Keyword(s):

Proximal Tubule ◽

Interleukin 1Β ◽

Converting Enzyme ◽

Proximal Tubule Cells ◽

Enzyme Family ◽

Tubule Cells ◽

Induced Apoptosis

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ATP Induces IL-1βSecretion inNeisseria gonorrhoeae-Infected Human Macrophages by a Mechanism Not Related to the NLRP3/ASC/Caspase-1 Axis

Mediators of Inflammation ◽

10.1155/2016/1258504 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Killen García ◽

Gisselle Escobar ◽

Pablo Mendoza ◽

Caroll Beltran ◽

Claudio Perez ◽

...

Keyword(s):

Immune Responses ◽

Immune Evasion ◽

Transcriptional Activation ◽

Pore Formation ◽

Human Monocyte ◽

Positive Staining ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Caspase 1

Neisseria gonorrhoeae(Ngo) has developed multiple immune evasion mechanisms involving the innate and adaptive immune responses. Recent findings have reported that Ngo reduces the IL-1βsecretion of infected human monocyte-derived macrophages (MDM). Here, we investigate the role of adenosine triphosphate (ATP) in production and release of IL-1βin Ngo-infected MDM. We found that the exposure of Ngo-infected MDM to ATP increases IL-1βlevels about ten times compared with unexposed Ngo-infected MDM (P<0.01). However, we did not observe any changes in inflammasome transcriptional activation of speck-like protein containing a caspase recruitment domain (CARD) (ASC,P>0.05) and caspase-1 (CASP1,P>0.05). In addition, ATP was not able to modify caspase-1 activity in Ngo-infected MDM but was able to increase pyroptosis (P>0.01). Notably ATP treatment defined an increase of positive staining for IL-1βwith a distinctive intracellular pattern of distribution. Collectively, these data demonstrate that ATP induces IL-1βsecretion by a mechanism not related to the NLRP3/ASC/caspase-1 axis and likely is acting at the level of vesicle trafficking or pore formation.

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Salmonella-Induced Caspase-2 Activation in Macrophages

Journal of Experimental Medicine ◽

10.1084/jem.192.7.1035 ◽

2000 ◽

Vol 192 (7) ◽

pp. 1035-1046 ◽

Cited By ~ 114

Author(s):

Veronika Jesenberger ◽

Katarzyna J. Procyk ◽

Junying Yuan ◽

Siegfried Reipert ◽

Manuela Baccarini

Keyword(s):

Type Iii Secretion ◽

Caspase 3 ◽

Secretion System ◽

Caspase 1 ◽

Chemical Inhibition ◽

Induction Of Apoptosis ◽

Caspase 2 ◽

Induced Apoptosis

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1–deficient macrophages undergo apoptosis within 4–6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1–independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1–dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1–dependent and –independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1–independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.

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In vivo study of motoneuron death induced by nerve injury in mice deficient in the caspase 1/ interleukin-1β-converting enzyme

Neuroscience ◽

10.1016/s0306-4522(00)00100-7 ◽

2000 ◽

Vol 98 (3) ◽

pp. 573-583 ◽

Cited By ~ 16

Author(s):

F. de Bilbao ◽

P. Giannakopoulos ◽

A. Srinivasan ◽

M. Dubois-Dauphin

Keyword(s):

Nerve Injury ◽

Interleukin 1Β ◽

In Vivo Study ◽

Converting Enzyme ◽

Caspase 1

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Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Science ◽

10.1126/science.aau1330 ◽

2019 ◽

Vol 364 (6435) ◽

pp. eaau1330 ◽

Cited By ~ 89

Author(s):

Andrew Sandstrom ◽

Patrick S. Mitchell ◽

Lisa Goers ◽

Edward W. Mu ◽

Cammie F. Lesser ◽

...

Keyword(s):

Innate Immunity ◽

Ubiquitin Ligase ◽

Shigella Flexneri ◽

Inflammasome Activation ◽

Anthrax Lethal Toxin ◽

Degradation Model ◽

Amino Terminal ◽

Caspase 1 ◽

Carboxyl Terminal ◽

Necessary And Sufficient

Inflammasomes are multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, aShigella flexneriubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

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Lipopolysaccharide Activates Caspase-1 (Interleukin-1–Converting Enzyme) in Cultured Monocytic and Endothelial Cells

Blood ◽

10.1182/blood.v91.2.577 ◽

1998 ◽

Vol 91 (2) ◽

pp. 577-584 ◽

Cited By ~ 110

Author(s):

Ralf R. Schumann ◽

Claus Belka ◽

Dirk Reuter ◽

Norbert Lamping ◽

Carsten J. Kirschning ◽

...

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Interleukin 1 ◽

Cysteine Proteases ◽

Precursor Protein ◽

Converting Enzyme ◽

Blood Monocytes ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Caspase 1

Abstract Interleukin-1β (IL-1β) is a pleiotropic proinflammatory cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature precursor protein into an active secretory form by the intracellular protease caspase-1 (formerly termed IL-1–converting enzyme [ICE]). Caspase-1 belongs to a rapidly growing family of cysteine proteases with substrate specificity for aspartate involved in cellular apoptosis. We have used an assay determining the caspase-1 activity based on cleavage of a fluorogenic peptide substrate to elucidate its role in lipopolysaccharide (LPS)-induced secretion of IL-1β. We show that LPS induces moderate caspase-1 activity in the monocytic cell line THP-1, in freshly isolated peripheral blood monocytes, and in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent fashion. Caspase-1 activation by LPS was associated with cleavage of the IL-1β precursor protein that was followed by release of the mature IL-1β protein in monocytic cells. In contrast, subsequent release of IL-1β by HUVECs was not significant. LPS-induced caspase-1 activation appeared not to result from modulation of caspase-1 transcript accumulation and inhibition of caspase-1 activity was accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable of alleviating the release of mature IL-1β. Taken together, these results show that LPS moderately activates caspase-1 and that caspase-1 activation contributes to LPS induction of IL-1β secretion.

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