EC:3.4.22.36 - FACTA Search

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1beta converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1beta, an 80% reduction of IL-8, and an 88% reduction in mean TNFalpha mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1beta. TNFalpha production was induced in the non-CD14+ population and there was no induction of TNFbeta by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFalpha was inhibited by IL-10. In the presence of IFNgamma, IL-18-induced TNFalpha was enhanced and there was an increase in the mature form of IL-1beta. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population.
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PMID:Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. 944 7

Apoptosis is programed cell death characterized by certain cellular changes and regulated by various gene products including Bcl-2 and caspase-1. The marijuana cannabinoid, Delta9tetrahydrocannabinol (THC), has been reported to suppress in culture the proliferation of splenocytes and increase the release of IL-1 from macrophages; however, the mechanisms of these effects remain unclear. Because cannabinoids have also been reported to induce apoptosis and because the release of IL-1 and suppression of lymphoproliferation are related to apoptosis, we tested for the induction of apoptosis by THC in murine immune cell cultures. Splenocytes cultured with Con A for up to 24 hr showed evidence of DNA fragmentation determined by gel electrophoresis, terminal deoxynucleotide transferase-mediated dUTP-fluorescein nick end labeling and 3H-thymidine labeling and THC (15-30 microM) treatment increased fragmentation under these conditions. Resident peritoneal macrophages cultured with lipopolysaccharides showed no obvious fragmentation unless they were also treated with THC. Time course studies examining DNA fragmentation and cell membrane integrity (assessed by dye exclusion) showed that fragmentation preceded membrane damage indicating that THC induced apoptosis rather than cell necrosis. In addition, THC treatment of splenocytes resulted in a decrease of Bcl-2 mRNA and protein as measured by Northern and Western blotting, respectively, and the drug induced apoptosis was blocked by the caspase inhibitor, Ac-Tyr-Val-Ala-L-aspartic acid aldehyde. These data suggest that THC treatment of cultured immune cells induces apoptosis through the regulation of Bcl-2 and caspase activity.
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PMID:Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. 969 74

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50

Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.
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PMID:IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. 989 78

When injected intravenously into humans and animals, interleukin-1 beta (IL-1 beta) is perhaps the most potent of the endogenous pyrogens. However, IL-1 beta is initially synthesized as a relatively inactive precursor molecule (proIL-1 beta) which lacks a signal peptide and hence remains inside the cell. To be active as a fever-producing molecule, proIL-1 beta must first be processed to an active mature molecule and secreted. Although several enzymes associated with inflammatory tissues are capable of processing proIL-1 beta into an active molecule in the extracellular compartment, the IL-1 beta converting enzyme (ICE, also called caspase-1) cuts intracellular proIL-1 beta after the aspartic acid residue in position 116, resulting in a highly active mature IL-1 beta that is secreted into the extracellular space. IL-18 is also initially synthesized as an inactive precursor molecule (proIL-18) lacking a signal peptide. IL-18 is a member of the IL-1 family, and like IL-1 beta, proIL-18 is cleaved by ICE to yield an active molecule. However, unlike IL-1 beta, IL-18 is not an endogenous pyrogen following intraperitoneal injection into mice. Nevertheless, IL-18 may contribute to inflammation and fever because IL-18 is a potent inducer of tumor necrosis factor, chemokines, and interferon-gamma production.
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PMID:Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. 991 59

NF-kappa B is involved in the transcriptional control of various genes that act as extrinsic and intrinsic survival factors for T cells. Our findings show that suppression of NF-kappa B activity with cell-permeable SN50 peptide, which masks the nuclear localization sequence of NF-kappa B1 dimers and prevents their nuclear localization, induces apoptosis in resting normal human PBL. Inhibition of NF-kappa B resulted in the externalization of phosphatidylserine, induction of DNA breaks, and morphological changes consistent with apoptosis. DNA fragmentation was efficiently blocked by the caspase inhibitor Z-VAD-fmk and partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is caspase-dependent. Interestingly, apoptosis induced by NF-kappa B suppression, in contrast to that induced by TPEN (N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the absence of active death effector proteases caspase-1-like (IL-1 converting enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA fragmentation factor-45. These findings suggest either low level of activation is required or that different caspases are involved. Preactivation of T cells resulting in NF-kappa B nuclear translocation protected cells from SN50-induced apoptosis. Our findings demonstrate an essential role of NF-kappa B in survival of naive PBL.
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PMID:Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3. 1039 45

The complete coding sequence of rainbow trout IL-1beta has been obtained. The gene contains a short 5' UTR (97 bp), a 780 bp open reading frame and a 466 bp 3' UTR, which includes a polyadenylation signal, 7 ATTTA motifs and an 18 bp poly A tail. The predicted amino acid sequence (260 amino acids) contains 3 potential glycosylation sites, with a predicted molecular weight of 29 kDa, and shows between 49 and 56% amino acid similarity to mammalian IL-1betas and 57% similarity to carp IL-1beta. Greatest homology was apparent within the secondary structure of the gene, with few of the amino acids known to bind to the IL-1 receptor being conserved. No ICE cut site was apparent but multiple alignment with mammalian sequences allowed a putative mature peptide of 166 amino acids to be identified, in which Ala(95)would be the amino terminus. Northern blot analysis showed that whilst no IL-1beta expression was detectable in head kidney leukocytes immediately after isolation, expression could be induced by stimulation with LPS for 4 h in culture. Similarly, with isolated head kidney macrophages expression was significantly increased following stimulation with LPS.
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PMID:Molecular cloning of interleukin 1beta from rainbow trout Oncorhynchus mykiss reveals no evidence of an ice cut site. 1043 1

The temporal and anatomical distribution of members of the interleukin-1 system in the rat brain following intraperitoneal kainic acid administration was studied in relation to neurodegeneration as detected with in situ end labelling. Kainic acid administration (10 mg/kg, i.p.) resulted in the induced expression of interleukin-1beta, interleukin- receptor antagonist and caspase-1p10 immunoreactivity in areas known to display neuronal and tissue damage upon excitotoxic lesions. The induction of these proteins was transient. Interleukin-1 immunoreactivity appeared at 5 h, and the interleukin-1 receptor antagonist-immunoreactive cells were first detected at 12 h, whereas the induction of caspase- 1p10 expression was first detected 24 h after kainic acid injection. Double labelling with the microglial marker Ox42 confirmed that both interleukin-1beta and interleukin-1 receptor antagonist were mainly localized in microglial cells. The regional distribution of in situ end-labelled neurons was similar to the distribution of cells expressing interleukin-1beta and interleukin-1 receptor antagonist, whereas the distribution of caspase-1 was more limited. The in situ end-labelled neurons, were, similarly to the interleukin-1beta-positive cells, first detected at 5 h, which is earlier than the induction of caspase-1. Our results show that the induction of IL-1beta and IL-1 receptor antagonist proteins after kainic acid are closely associated with the temporal as well as the anatomical distribution of in situ end-labelled neurons, whereas the induction of caspase-1 protein exhibited a delayed temporal profile and limited distribution. Since cytokine production occurs in activated microglial cells, the inflammatory component seems to be a strong mediator of this type of excitotoxic damage. The late onset of the caspase-1 expression would seem to indicate that this enzyme has no fundamental role in directly causing neuronal cell death induced by systemic kainic acid.
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PMID:Immunohistochemical localization of interleukin-1beta, interleukin-1 receptor antagonist and interleukin-1beta converting enzyme/caspase-1 in the rat brain after peripheral administration of kainic acid. 1047 57

Interleukin (IL)-18 is a newly discovered cytokine, structurally similar to IL-1, with profound effects on T-cell activation. This short review summarizes the present knowledge on IL-18, to give an insight into the future perspectives for its possible use as vaccine adjuvant. Formerly called interferon (IFN) gamma inducing factor (IGIF), IL-18 is the new name of a novel cytokine that plays an important role in the T-cell-helper type 1 (Th1) response, primarily by its ability to induce IFNgamma production in T cells and natural killer (NK) cells. Mice deficient in IL-18 have suppressed IFNgamma production despite the presence of IL-12 IL-18 is related to the IL-1 family in terms of structure, receptor family, and function. In terms of structure, IL-18 and IL-1beta share primary amino acid sequences of the so-called "signature sequence" motif and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide which requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE, also called caspase-1). The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of tumor necrosis factor (TNF), IL-1, Fas ligand, and several chemokines. The activity of IL-18 is via an IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-1 receptor family previously identified as the IL-1 receptor-related protein (IL-1Rrp), and a signaling chain, also a member of the IL-1R family. The IL-18R complex recruits the IL-1R-activating kinase (IRAK) and TNFR-associated factor-6 (TRAF-6) which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase (NIK) with subsequent activation of NFkappaB. Thus on the basis of primary structure, three-dimensional structure, receptor family, signal transduction pathways and biological effects, IL-18 appears to be a new member of the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.
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PMID:Interleukin-18. 1052 48

Mechanisms that regulate conversion of prointerleukin-1beta (pro-IL-1beta) to its mature form by the cysteine protease caspase-1 are not well understood. In this study, we demonstrate that mature caspase-1 subunits are produced when human monocytes are treated with ATP and, like mature IL-1beta, are released extracellularly. Characterization of the pharmacological sensitivity of this stimulus-coupled response revealed that some caspase-1 inhibitors allow pro-IL-1beta secretion, whereas others do not. Two nonselective alkylating agents, N-ethylmaleimide and phenylarsine oxide, also blocked maturation and release of pro-IL-1beta. Two inhibitors of anion transport, glyburide and ethacrynic acid, blocked maturation of both caspase-1 and pro-IL-1beta and prevented release of the propolypeptides. Procaspase-3 was detected in monocyte extracts, but its proteolytic activation was not efficient in the presence of ATP. Maturation of procaspase-1 and release of the mature enzyme subunits therefore accompany stimulus-coupled human monocyte IL-1 post-translational processing. Agents that appear to selectively inhibit mature caspase-1 do not prevent ATP-treated cells from releasing their cytosolic components. On the other hand, anion transport inhibitors and alkylating agents arrest ATP-treated monocytes in a state where membrane latency is maintained. The data provided support the hypothesis that stimulus-coupled IL-1 post-translational processing involves a commitment to cell death.
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PMID:ATP treatment of human monocytes promotes caspase-1 maturation and externalization. 1060 Dec 48

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