A Broad-Spectrum Caspase Inhibitor Attenuates Allergic Airway Inflammation in Murine Asthma Model

Iwata, Akiko; Nishio, Kazumi; Winn, Robert K.; Emil, Y.; Henderson, William R.; Harlan, John M.

doi:10.4049/jimmunol.170.6.3386

Cited by 51 publications

(45 citation statements)

References 41 publications

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“…71). For example, zVAD diminished mouse T cell proliferation, but not activation (72), and a recent study in an asthma mouse model attributed the beneficial in vivo effects of zVAD to the inhibition of T cell activation (73). In our hands, the levels of LCMV-specific CD8 ϩ T cells were similar in zVAD-treated and nontreated mice at all times, and our data do not support a major role for caspases in T cell proliferation.…”

Section: Discussionsupporting

confidence: 55%

“…In brief, cells from blood, lymph nodes, or spleens of LCMV-infected or naive mice were isolated as described above, then were incubated in round-bottom 96-well plates at 37°C, 5% CO 2 , for 5-7 h in the presence or absence of peptide in RPMI 1640 (containing 5-10% FBS, 100 M 2-ME, L-glutamine, and antibiotics). The peptides, used at a final concentration of 1-2 g/ml, represent dominant and subdominant CD8 ϩ T cell epitopes from LCMV: NP 118 [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] and NP 309 -328 (both H-2A b ). Brefeldin A (Sigma) was added to a final concentration of 5 g/ml.…”

Section: Intracellular Cytokine Staining (Iccs)mentioning

confidence: 99%

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The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

Nussbaum

Whitton

2004

The Journal of Immunology

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The effectiveness of protection conferred by CD8+ memory T cells is determined by both their quality and their quantity, which suggests that vaccine efficacy might be improved if it were possible to increase the size of the memory pool. Approximately 90% of virus-specific CD8+ T cells die during the contraction phase and, herein, we have attempted to increase the memory pool by reducing CD8+ T cell death. CD8+ T cell contraction has been attributed to apoptosis, or programmed cell death (PCD), which, classically, is dependent on caspases. Caspase-dependent PCD can be prevented by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (zVAD), and here we evaluate the effect of this compound on virus-specific T cell responses in mice. zVAD prevented caspase-dependent PCD of freshly isolated virus-specific T cells in tissue culture, and a fluorescent analog, FITC-VAD, entered CD8+ T cells following in vivo injection. However, despite using 11 different regimens of zVAD administration in vivo, no significant effects on CD8+ or CD4+ memory T cell numbers were observed. Furthermore, the CD8+ memory T cell responses to secondary virus infection were indistinguishable, both qualitatively and quantitatively, in zVAD-treated and normal mice. The absence of effect cannot be attributed to a technical flaw, because identical doses of zVAD were able to rescue mice from hepatocyte apoptosis and lethal intrahepatic hemorrhage, induced by inoculation of anti-Fas Ab. We conclude that the contraction phase of the virus-specific T cell response is unlikely to require caspase-dependent PCD. We propose that contraction can be mediated by an alternative, caspase-independent pathway(s).

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Section: Discussionsupporting

confidence: 55%

Section: Intracellular Cytokine Staining (Iccs)mentioning

confidence: 99%

The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

Nussbaum

Whitton

2004

The Journal of Immunology

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“…Finally, consistent with the observation that the activation of caspases can occur rapidly in vivo, e.g., within 2 hours in renal I/R (38), we found that caspase inhibitor Z-VAD-fmk and noncleavable PARP-1 show a protective effect in our I/R models. These findings are reminiscent of previous studies showing that caspase inhibitors attenuate the mouse response to septic shock, focal and renal I/R, and allergic airway inflammation in the asthma model (38)(39)(40)(41)(42)(43). Although each of these studies has proposed a different mechanism, all of them are linked to the prevention of cell apoptosis.…”

Section: Discussionsupporting

confidence: 59%

“…Application of caspase inhibitors has been shown to attenuate intestinal and renal tissue injuries (in our study) and other pathophysiological processes (39)(40)(41)(42)(43). The present study, using a genetically engineered mouse model, in which PARP-1 cleavage is abolished, provides novel insights into the significance of caspase cleavage of PARP-1 and highlights the importance of PARP-1 in inflammation and tissue injury.…”

Section: Discussionmentioning

confidence: 78%

Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice

Pétrilli

Herceg²,

Hassa³

et al. 2004

J. Clin. Invest.

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Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADPribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1 KI/KI ) mouse model, in which the caspase cleavage site of PARP-1, DEVD 214 , was mutated to render the protein resistant to caspases during apoptosis. While PARP-1 KI/KI mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-κB to DNA, NF-κB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies. IntroductionUpon DNA damage, poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30) is activated and catalyzes the formation of poly(ADPribose) (PAR) chains by transferring (ADP-ribose) from β-NAD + onto itself and nuclear acceptor proteins (1). PARP-1 is known to be involved in various cellular processes including DNA repair, recombination, genomic stability, transcription regulation, and cell death (1-3). In addition, massive poly(ADP-ribosyl)ation induced by acute DNA damage results in rapid depletion of cellular NAD + and ATP pools, which, if not regulated, can lead to cellular dysfunction and cell death (4). Involvement of PARP-1 in cell death is also speculated based on the prominent phenomenon that during apoptosis, PARP-1 is cleaved by caspases at the conserved site DEVD 214 , generating 24-kDa and 89-kDa fragments, a hallmark of apoptosis.Mice lacking PARP-1 develop normally and PARP-1 -/-fibroblasts and lymphoid cells display a normal apoptotic response after treatment with various apoptotic inducers, such as anti-Fas antibody, TNF-α, γ-radiation, and dexamethasone, which demonstrates that PARP-1 per se is dispensable for apoptosis, at least in these cell types (5, 6). However, inactivation of PARP-1 by chemical inhibitors and genetic means protects mice from endotoxic shock and other disease models related to inflammation, such as diabetes, stroke, and myocardial reperfusion (7-12). In addition, PARP inhibitors protect rats from renal and intestinal ischemia-

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“…R odent models for human allergies, including atopic dermatitis (1), asthma (2), allergic rhinitis (3), and food allergies (4,5), have allowed researchers to elucidate important fundamental principles of the cellular and molecular mechanisms of these diseases. However, it was suggested that animal models do not always reflect all aspects of human allergic diseases because of differences between species.…”

mentioning

confidence: 99%

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

Ito

Takahashi

Katano

et al. 2013

The Journal of Immunology

134

128

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The development of animal models that mimic human allergic responses is crucial to study the pathophysiology of disease and to generate new therapeutic methodologies. Humanized mice reconstituted with human immune systems are essential to study human immune reactions in vivo and are expected to be useful for studying human allergies. However, application of this technology to the study of human allergies has been limited, largely because of the poor development of human myeloid cells, especially granulocytes and mast cells, which are responsible for mediating allergic diseases, in conventional humanized mice. In this study, we developed a novel transgenic (Tg) strain, NOD/Shi-scid-IL2rγnull (NOG), bearing human IL-3 and GM-CSF genes (NOG IL-3/GM–Tg). In this strain, a large number of human myeloid cells of various lineages developed after transplantation of human CD34+ hematopoietic stem cells. Notably, mature basophils and mast cells expressing FcεRI were markedly increased. These humanized NOG IL-3/GM–Tg mice developed passive cutaneous anaphylaxis reactions when administered anti–4-hydroxy-3-nitrophenylacetyl IgE Abs and 4-hydroxy-3-nitrophenylacetyl. More importantly, a combination of serum from Japanese cedar pollinosis patients and cedar pollen extract also elicited strong passive cutaneous anaphylaxis responses in mice. Thus, to our knowledge, our NOG IL-3/GM–Tg mice are the first humanized mouse model to enable the study of human allergic responses in vivo and are excellent tools for preclinical studies of allergic diseases.

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A Broad-Spectrum Caspase Inhibitor Attenuates Allergic Airway Inflammation in Murine Asthma Model

Cited by 51 publications

References 41 publications

The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

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