Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock

Li, Ping; Allen, Hamish; Banerjee, Subhashis; Franklin, Simon; Herzog, Linda; Johnston, Cynthia; McDowell, J. J.; Paskind, Michael; Rodman, Laura; Salfeld, Jochen; Towne, E. Gene; Tracey, Daniel E.; Wardwell, Scott; Wei, Feng-Yi; Wong, Winnie W.; Kamen, Robert; Seshadri, Tara

doi:10.1016/0092-8674(95)90490-5

Cited by 1,353 publications

(998 citation statements)

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“…Although most of our experiments were performed with transfected cells, several findings suggest that these results are also relevant for the endogenous proteins: (i) Asc is an essential activator of procaspase-1 in macrophages, 15 and Asc is also expressed by COS-1 cells and human primary keratinocytes (our own unpublished results); (ii) NALP1 belongs to a family of 14 members 32 and at least NALP1 is expressed by human primary keratinocytes (results not shown); (iii) proIL-1b secretion and activation is strictly dependent on the expression of procaspase-1 in vivo 8 and also in our experiments; (iv) endogenous EBBP is also secreted by primary keratinocytes and macrophages (results not shown); and (v) endogenous EBBP and IL-1b colocalize in keratinocytes and macrophages (results not shown) and interact with each other, at least in monocytes (Figure 3). Finally, downregulation of endogenous EBBP in COS-1 cells or human primary keratinocytes using siRNA reduced the level of secreted IL-1b ( Figures 5 and 6), demonstrating that also endogenous EBBP is involved in proIL-1b maturation.…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2006

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The estrogen-responsive B box protein (EBBP) and Pyrin belong to a family of structurally related proteins. While mutations in the pyrin gene cause an autoinflammatory disease, the biological function of EBBP is unknown. In this study, we identified the proinflammatory cytokine interleukin1b (IL-1b) as an EBBP-binding partner. Furthermore, caspase-1 and NACHT, LRR and Pyrin domain containing protein (NALP) 1, two components of the recently identified inflammasome, a platform for the activation of caspase-1, also interact with EBBP. These proteins bind to the RFP domain of EBBP, suggesting that this domain of so far unknown function is an important protein-binding domain. EBBP was secreted in a caspase-1-dependent manner from cultured cells, and its secretion was enhanced by IL-1b. Vice versa, endogenous and overerexpressed EBBP increased IL-1b secretion. These results provide evidence for a role of EBBP in innate immunity by enhancing the alternative secretion pathway of IL-1b.

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Section: Discussionmentioning

confidence: 93%

“…6,7 Consequently, macrophages from caspase-1 knockout mice cannot produce mature IL-1b. 8 Caspase-1 itself is expressed as an inactive precursor. Recently, it was shown that activation of procaspase-1 and subsequent processing of proIL-1b in a cell-free system from macrophages is dependent on a protein complex called the inflammasome.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…[12][13][14][15] These mice have a defect in the maturation of proIL-1b and proIL-18 and are resistant to the lethal effect of endotoxins. IL-18 was first described as an endotoxininduced factor that stimulates the production of interferon-g by splenocytes.…”

Section: Caspase-1 and It Substrate Il-1bmentioning

confidence: 99%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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“…50,51 In support of the role of caspase-1 in IL-18 maturation, caspase-1 knockout mice (caspase-1 À/À ) have been found to be resistant to endotoxic shock and unable to release IL-1b, IFN-g, and IL-18 in response to bacterial endotoxin. 52 However, evidence increasingly indicates that the requirement of caspase-1 for IL-1b and IL-18 production is stimulus dependent. Caspase-1 À/À mice released a normal amount of IL-1b and IFN-g when stimulated with ConA.…”

Section: Discussionmentioning

confidence: 99%

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

et al. 2003

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Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)-induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConAinduced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b + inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4 + cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.

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Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock

Cited by 1,353 publications

References 45 publications

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

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

Inflammatory caspases and inflammasomes: master switches of inflammation

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

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