Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-18, a potent IFN-gamma-inducing cytokine, is expressed by various nonimmune cells as well as macrophages, suggesting that it has important physiological and immunological roles. The present study focused on the mechanism of active IL-18 induction from human oral epithelial cells. The epithelial cells and the cell lines constitutively express IL-18 mRNA and the 24-kDa precursor form of IL-18. Bioactive IL-18 exhibiting IFN-gamma-inducing activity was detected in the supernatant of the cells on costimulation with neutrophil proteinase 3 (PR3) and LPS for 24 h after IFN-gamma-priming for 3 days. An active 18-kDa form of IL-18 was detected in lysate and supernatant of the cells only after the above treatment and the induction was inhibited by cycloheximide and by serine proteinase inhibitors. After the treatment, lactate dehydrogenase activity was not detected in the cell culture supernatant, and PR3 was detected only in the membrane and not in cytoplasm fractions of the cells. Caspase-1 was not detected in the cells even after the treatment and the IL-18 induction was not inhibited by a caspase-1 inhibitor. These results suggest that the PR3-mediated induction of bioactive IL-18 secretion from oral epithelial cells in combination with LPS after IFN-gamma-priming occurred via a caspase-1-independent pathway, and provide new insight into the possible involvement of a neutrophil proteinase in the induction of bioactive IL-18 in oral inflammation such as periodontitis.
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PMID:Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. 1171 26

IL-18, which requires cleavage with caspase-1 to become active, was originally discovered as a factor that enhances IFN-gamma production from Th1 cells in the presence of anti-CD3 or anti-TcR Ab. However, it was later shown that IL-12 and IL-18 without TcR engagement can induce IFN-gamma in Th1 cells and nonpolarized T cells. Additional TcR engagement has no effect on this IFN-gamma response. Furthermore, a combination of IL-12 and IL-18 acts on B cells, NK cells, macrophages and dendritic cells to produce IFN-gamma. In contrast, IL-18 without help from IL-12 induces Th2 cytokines in T cells and NK cells. Moreover, IL-18 directly stimulates basophils and mast cells to produce Th2 cytokines and histamine independently of IgE. Most surprisingly, IL-18 causes high-level IgE production when administered to normal mice by causing CD4+ T cells to produce IL-4 and to express CD 40 ligand. We established skin-specific caspase-1 transgenic mice with elevated levels of IL-18 in their sera. We found high serum level of IgE, which is entirely dependent on stat 6 in these transgenic mice. These results indicate that caspase-1/IL-18 may be critically involved in regulation of IgE production in vivo, providing a potential therapeutic target for allergic disorders.
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PMID:[Regulation of Th1 and Th2 immune responses by IL-18]. 1190 33

The epidermal Langerhans cells (LC), a member of the dendritic cell family, and the LC-derived cytokine IL-12 play a pivotal role in the initiation of contact hypersensitivity (CHS), a Th1 immune response in the skin. Because IL-18, another LC-derived cytokine, shares functional and biological properties with IL-12, we examined a potential role for IL-18 in CHS initiation. Our studies demonstrated that during the induction phase of murine CHS, IL-18 mRNA was significantly up-regulated in the skin-draining lymph nodes (LN). Migratory hapten-modified LC in LN expressed high levels of IL-18 mRNA and secreted functional IL-18 protein. LN cells produced significant amounts of IFN-gamma following in vitro IL-12 stimulation, which could be partially blocked by anti-IL-18 Ab, suggesting a synergistic role for endogenous IL-18 in IFN-gamma production by LN cells. Because mature IL-18 requires cleavage of immature precursors by caspase-1, we further examined IL-12-induced IFN-gamma production in caspase-1(-/-) LN cells. An impaired IFN-gamma production was seen in caspase-1(-/-) LN cells, which could be restored by addition of exogenous IL-18, supporting a role for caspase-1-cleaved, mature IL-18 in IFN-gamma production. Finally, in vivo studies showed that CHS responses were significantly inhibited in mice treated with neutralizing IL-18 Ab as well as in caspase-1(-/-) mice deficient in mature IL-18, indicating functional relevance for IL-18 in CHS. Taken together, our studies demonstrate that LC-derived IL-18 significantly contributes to CHS initiation.
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PMID:Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity. 1190 86

Interleukin (IL)-18 is a member of the IL-1 cytokine family. Pro-IL-18 is cleaved by caspase-1 (IL-1beta-converting enzyme) to yield biologically active 18-kDa IL-18. Interleukin-18 is recognized by a heterodimeric receptor, consisting of a ligand-binding alpha-chain (IL-18Ralpha/IL-1Rrp) and an associating beta-chain (IL-18Rbeta/AcPL), which transmits signals through MyD88/IRAK/TRAF-6 molecules. Interleukin-18 is expressed in various types of cells, including macrophages, keratinocytes, intestinal epitherial cells, osteoblastic cells, chondrocytes, and adrenal cortex cells. Interleukin-18 promotes IFN-gamma production and Th1 helper T-cell development, synergistically with IL-12. However, IL-18 itself shows capabilities to induce IL-4, IL-5, IL-10, and IL-13 from T and natural killer cells. It also induces PGE2 production from activated macrophages. Moreover, many diseases are characterized by the production of IL-18 in the lesion. Taking these data together, our working hypothesis on how IL-18 is involved in "destructive" and "compensatory" pathways is proposed in this issue.
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PMID:Roles of interleukin-18 in tissue destruction and compensatory reactions. 1204 45

We have recently reported the identification of four novel members of the interleukin-1 (IL-1) family which we designated as IL-1 homologue 1-4 (IL-1H1-4). These proteins exhibit significant sequence homology to other members of the IL-1 family. Of these homologues, only IL-1H4 (renamed IL-1F7b) was predicted to contain a propeptide domain and a caspase cleavage site. We now report that caspase-1 cleaves IL-1F7b at the predicted site to generate mature IL-1F7b. Caspase-4 was also able to process IL-1F7b, albeit inefficiently. Other caspases and Granzyme-B did not cleave IL-1F7b. Furthermore, adenovirus-mediated expression of IL-1F7b in HEK 293 cells led to in situ processing and secretion of mature IL-1F7b. In a screen to identify a potential receptor, both pro and mature IL-1F7b bound to the soluble IL-18 receptor alpha-Fc (IL-18Ralpha-Fc) but not to the soluble IL-1R-Fc or ST2R-Fc fusion proteins. Mature IL-1F7b bound to the IL-18Ralpha-Fc protein with higher affinity than the pro form, although the affinities for both proteins were significantly lower than that observed for IL-18. Consistent with this observation, only IL-18 and not IL-1F7b induced IFN-gamma production by KG1a cells. We also report that pro and mature IL-1F7b form homodimers with association constants of 4 microM and 5 nM, respectively, suggesting biological relevance to IL-1F7b processing. Finally, we have localized the expression of IL-1F7b protein in discrete cell populations including plasma cells and tumor cells. These data suggest that IL-1F7b may be involved in immune response, inflammatory diseases and/or cancer.
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PMID:Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. 1209 20

Amebiasis is a major cause of morbidity and mortality worldwide. Invasion by Entamoeba histolytica trophozoites causes secretion of proinflammatory cytokines from host epithelial cells, leading to a local acute inflammatory response, followed by lysis of colonic cells. Extracellular cysteine proteinases from amebic trophozoites are key virulence factors and have a number of important interactions with host defenses, including cleavage of immunoglobulin G (IgG), IgA, and complement components C3 and C5. Amebic lysates have also been shown to activate the precursor to interleukin 1-beta (proIL-1beta), mimicking the action of caspase-1. IL-18 is also a central cytokine, which induces gamma interferon (IFN-gamma) and activates macrophages, one of the main host defenses against invading trophozoites. Because proIL-18 is also activated by caspase-1, we evaluated whether amebic proteinases had a similar effect. Instead, we found that recombinant proIL-18 was cleaved into smaller fragments by the complex of surface-associated and released amebic proteinases. To evaluate the function of an individual proteinase from the complex pool, we expressed an active surface proteinase, EhCP5, which is functional only in E. histolytica. Recombinant EhCP5 expressed in Pichia pastoris had kinetic properties similar to those of the native enzyme with respect to substrate specificity and sensitivity to proteinase inhibitors. In contrast to the activation of proIL-1beta by amebic lysates, the purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive fragments. These studies suggest that the acute host response and amebic invasion result from a complex interplay of parasite virulence factors and host defenses. E. histolytica may block the host inflammatory response by a novel mechanism, inactivation of IL-18.
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PMID:A surface amebic cysteine proteinase inactivates interleukin-18. 1259 42

Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
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PMID:Interleukin-18 and host defense against infection. 1279 54

Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma, whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
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PMID:Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma. 1279 66

To investigate the intra-hepatic activation of the IFN system in patients affected by chronic HCV-infection in comparison with that observed in a non-infectious liver disease such as non-alcoholic steatohepatitis, we measured the liver steady state mRNA levels of interferon-alpha, interferon-beta and interferon-gamma as well as of IFN-related genes (IFNAR-1, STAT1alpha, PKR, 2-5 AS, IRF-1, ICE and IL-18). In HCV-infected subjects, possible correlations of these parameters with viral load and liver injury were also analyzed. Twenty-four chronic untreated HCV-infected subjects and seven patients with non-alcoholic steatohepatitis were enrolled in the study. Liver biopsies were graded according to Knodell scores. Intra-hepatic mRNA levels of IFNs and related genes were assessed by semi-quantitative RT-PCR. In comparison with non-alcoholic steatohepatitis, in HCV-infected subjects IFN-alpha and -beta mRNA levels were significantly lower, whereas IFN-gamma, IFNAR-1, STAT1alpha IRF-1, and IL-18 mRNA were upregulated. Moreover, IFN-gamma mRNA steady state levels were correlated positively with those of IFNAR-1, IRF-1, and IL-18, suggesting a coordinated induction of these genes. Although plasma viral load was correlated inversely with IL-18-specific mRNA, viral load was not related to liver injury. IFN-gamma and IRF-1 mRNA levels were correlated positively with ALT, but not with the grading or staging. Conversely, IFN-alpha and -beta mRNA levels were higher in livers with lower staging scores. These findings support the hypothesis that in chronic HCV infection there is an imbalance between an upregulated IFN-gamma system and a downregulated IFN-alpha and -beta system, probably due to a mixed effect exerted by HCV-specific and inflammatory non-specific factors.
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PMID:Endogenous levels of mRNA for IFNs and IFN-related genes in hepatic biopsies of chronic HCV-infected and non-alcoholic steatohepatitis patients. 1279 20

Apoptosis plays an important role in immune responses, but little is known about its involvement in contact hypersensitivity (CH). In this study, we have investigated the role of Fas/Fas ligand (FasL)-mediated apoptosis in the pathogenesis of CH. Mice were sensitized by one topical application of 100 microl of 3% oxazolone to shaved skin of the abdomen. Six days later, CH was provoked by challenging both sides of sensitized mouse right ear with 15 microl of 1% oxazolone. Using a DNA ladder assay, we found that apoptosis was induced in the skin of oxazolone-sensitized mice 24-96 h after allergen challenge. Annexin V-fluorescein isothiocyanate (FITC)-propidium iodide (PI) apoptosis flow cytometric assay showed that early apoptotic CD4(+) T cells (annexin V-FITC(+)PI(-)), but not late apoptotic CD4(+) T cells (annexin V-FITC(+)PI(+)), increased in the inflamed skin of mice with CH. Moreover, the expressions of mRNAs for T helper (Th2) cytokine (interleukin (IL)-4), Th1 cytokine (interferon (IFN)-gamma) and proapoptotic molecules (Bax, Fas, FasL and IL-1beta-converting enzyme (ICE)/caspase-1) were significantly elevated in the oxazolone-sensitized mouse skin 6-72 h after allergen challenge. Dramatic increase in IL-10 mRNA was only observed in the sensitized mouse skin 6 and 12 h after allergen challenge. Furthermore, CH was significantly inhibited with decreased apoptosis and early apoptotic CD4(+) T cells in inflamed skin in Fas mutant lpr/lpr mice compared to wild-type mice, whereas there were no significant differences in IL-4, IFN-gamma, IL-10, Bax and ICE mRNAs in the inflamed skin of CH between lpr/lpr and wild-type mice. Our results thus suggest that Fas/FasL pathway partially contributes to apoptosis in murine CH and that Fas/FasL-mediated apoptosis plays a partial role in the development of CH. The contribution of Fas/FasL-mediated apoptosis to CH appears independent of Th1 and Th2 cytokines.
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PMID:Role of Fas/Fas ligand-mediated apoptosis in murine contact hypersensitivity. 1281 Mar 50


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