A Synthetic Inhibitor of Interleukin-lβ Converting Enzyme Prevents Endotoxin-Induced Interleukin-lβ Production<i>In Vitro</i>and<i>In Vivo</i>

Ds, Fletcher; Agarwal, Lily; Kt, Chapman; Chin, Jayne; La, Egger; Limjuco, G; Luell, Silvi; De, MacIntyre; Ep, Peterson; Na, Thornberry

doi:10.1089/jir.1995.15.243

Cited by 39 publications

(20 citation statements)

References 12 publications

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“…22,23 In contrast, no beneficial effects on LV myocyte structures and functions were observed when serum obtained from endotoxin-and zVAD.fmk-treated rats was used. This is consistent with either high cell permeability and serum short half-life 24,25 or absence of effects on immune response of small peptide caspase inhibitors. Caspase-3-like activation can be directly responsible for septic serum-induced cardiomyocyte contractile dysfunction.…”

Section: Discussionsupporting

confidence: 82%

“…Cell viability (trypan blue exclusion) and nuclear condensation (Hoechst 33342 staining, 1 g/mL) of LV cardiomyocytes isolated from control and endotoxin-treated rats were quantified over time. Cell viability in control and septic LV cardiomyocytes remained up to 80% over time (4,24, and 96 hours; data not shown). Few condensed nuclei (Hoechst staining) were detected (Ͻ5%) in control and septic LV cardiomyocytes at 4 and 24 hours after isolation (data not shown).…”

Section: Endotoxin Rat Treatment Induces Cardiomyocyte Caspase Activamentioning

confidence: 88%

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Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

et al. 2005

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Background-Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction. Methods and Results-LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca 2ϩ . Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3-like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk-or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk. Conclusions-The

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Section: Discussionsupporting

confidence: 82%

Section: Endotoxin Rat Treatment Induces Cardiomyocyte Caspase Activamentioning

confidence: 88%

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

et al. 2005

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“…However, the importance of TACE as a pivotal enzyme in the development of inflammatory responses is indisputable given the ability of TACE inhibitors to dramatically reduce circulating TNF␣ levels in endotoxin-treated rats and mice (1-3). The importance of ICE in inflammation is also well documented in studies reporting successful amelioration of inflammation in various animal models by inactivation of this enzyme, e.g., ICE inhibitors reduced systemic inflammation induced by endotoxin in mice (41) and ICE-deficient mice were resistant to endotoxic shock (42). In contrast, it was found that localized inflammation induced by turpentine application to the skin induced levels of the IL-1␤-dependent cytokine, IL-6, in ICE-deficient mice that were comparable to those of wild-type mice, whereas no IL-6 was produced in IL-1␤-deficient mice (16).…”

Section: Discussionmentioning

confidence: 91%

Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3

Coeshott

Ohnemus

Pilyavskaya

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

335

240

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Two important cytokines mediating inf lammation are tumor necrosis factor ␣ (TNF␣) and IL-1␤, both of which require conversion to soluble forms by converting enzymes. The importance of TNF␣-converting enzyme and IL-1␤-converting enzyme in the production of circulating TNF␣ and IL-1␤ in response to systemic challenges has been demonstrated by the use of specific converting enzyme inhibitors. Many inf lammatory responses, however, are not systemic but instead are localized. In these situations release and͞or activation of cytokines may be different from that seen in response to a systemic stimulus, particularly because associations of various cell populations in these foci allows for the exposure of procytokines to the proteolytic enzymes produced by activated neutrophils, neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (Cat G). To investigate the possibility of alternative processing of TNF␣ and͞or IL-1␤ by neutrophil-derived proteinases, immunoreactive TNF␣ and IL-1␤ release from lipopolysaccharide-stimulated THP-1 cells was measured in the presence of activated human neutrophils. Under these conditions, TNF␣ and IL-1␤ release was augmented 2-to 5-fold. In the presence of a specific inhibitor of NE and PR3, enhanced release of both cytokines was largely abolished; however, in the presence of a NE and Cat G selective inhibitor, secretory leucocyte proteinase inhibitor, reduction of the enhanced release was minimal. This finding suggested that the augmented release was attributable to PR3 but not NE nor Cat G. Use of purified enzymes confirmed this conclusion. These results indicate that there may be alternative pathways for the production of these two proinf lammatory cytokines, particularly in the context of local inf lammatory processes.

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“…Serum IL-18 levels were dependent upon the LPS dose, which is depicted on the upper x-axis so that IL-18 levels correlate with the corresponding stimulating dose of LPS. known to protect animals from lethal inflammation (11,41,42). In addition, the cas-1-inducing activity (Figs.…”

Section: Il-18 Levels and Cas-1 Activity Are Interdependentmentioning

confidence: 99%

IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression

Joshi

Kalvakolanu

Hasday

et al. 2002

The Journal of Immunology

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LPS enhanced antibacterial host defenses (ABHD) when given at low (75 μg) doses (16 of 19 mice survived 3× LD50 Escherichia coli vs 3 of 19 LPS-naive mice; p = 0.0001), but induced lethal inflammation at high (500 μg) doses (5 of 5 died). Differences in the cytokine profiles induced by these LPS doses may provide insight into the mechanism(s) of transition from beneficial to lethal LPS responses. The 75 μg LPS induced 5.9 ± 0.9 ng/ml serum IL-18 at 8 h, which decreased to 2.3 ± 0.4 ng/ml by 24 h, whereas 500 μg LPS induced 11.1 ± 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 μg, higher but sublethal (150 μg) doses of LPS induced greater serum IL-18 levels and less effectively induced ABHD (3 of 8 survived). Reduction of serum IL-18 with neutralizing Ab improved the ABHD induced by 150 μg, but reduced that produced by 75 μg LPS, suggesting an optimal range of serum IL-18 level was essential for efficient ABHD. Increased expression of caspase-1 mRNA in response to the higher IL-18 levels induced at the 150 and 500 μg, but not at the 75 μg doses of LPS may represent a positive feedback regulatory loop leading to sustained serum IL-18 levels. We conclude that the regulation of serum IL-18 expression is critical to the outcome of innate immune responses to LPS.

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A Synthetic Inhibitor of Interleukin-lβ Converting Enzyme Prevents Endotoxin-Induced Interleukin-lβ ProductionIn VitroandIn Vivo

Cited by 39 publications

References 12 publications

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3

IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression

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