scholarly journals The Absence of Tryptase Mcpt6 Causes Elevated Cellular Stress in Response to Modulation of the Histone Acetylation Status in Mast Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1190
Author(s):  
Santosh Martin ◽  
Rabelo Melo ◽  
Pejler
Keyword(s):  
Mast Cells ◽  
Histone Acetylation ◽  
Early Stage ◽  
Trichostatin A ◽  
Secretory Granules ◽  
Cellular Stress ◽  
Cell Stress ◽  
Wild Type ◽  
Acetylation Status ◽  
Core Histones

Mast cells contain large amounts of proteases stored within their secretory granules. Previously we showed that one of these proteases, tryptase, in addition to its location within granules, can also be found within the mast cell nucleus, where it has the capacity to affect the acetylation profile of nucleosomal core histones in aging cells. Based on this notion, and on the known sensitivity of mast cells to modulation of histone acetylation, we here asked whether tryptase could impact on the responses against cellular stress caused by disturbed histone acetylation status. To address this, wild-type and tryptase-deficient (Mcpt6−/−) mast cells were subjected to cell stress caused by trichostatin A (TSA), a histone deacetylase inhibitor. Wild-type and Mcpt6−/− mast cells were equally sensitive to TSA at an early stage of culture (~8 weeks). However, in aging mast cells (>50 weeks), tryptase-deficiency led to increased sensitivity to cell death. To address the underlying mechanism, we assessed effects of tryptase deficiency on the expression of markers for proliferation and cell stress. These analyses revealed aberrant regulation of thioredoxin, thioredoxin reductase, glutaredoxin, and glutathione reductase, as well as blunted upregulation of ribonucleotide reductase subunit R2 in response to TSA in aging cells. Moreover, the absence of tryptase led to increased expression of Psme4/PA200, a proteasome variant involved in the processing of acetylated core histones. Altogether, this study identifies a novel role for tryptase in regulating the manifestations of cell stress in aging mast cells.

Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

2006 ◽  
Vol 290 (3) ◽  
pp. E490-E493 ◽  
Author(s):  
Timothy A. Sato ◽  
Murray D. Mitchell
Keyword(s):  
Dna Methylation ◽  
Receptor Antagonist ◽  
Histone Acetylation ◽  
Trichostatin A ◽  
Cell Types ◽  
Causative Factor ◽  
Histone Deacetylation ◽  
The Other ◽  
Acetylation Status ◽  
Tnf Α

It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th2 immunological state. This can be activated in some cell types by modifying DNA methylation and histone acetylation status. We demonstrate that the molecular inhibition of histone deacetylation, using trichostatin A (TSA), in human choriodecidual explants leads to a massive increase in lipopolysaccharide (LPS)-stimulated IL-1β. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-α production or production of the other cytokines studied (IL-10, IL-1 receptor antagonist). The molecular inhibition of DNA methylation and histone deacetylation, using 5-aza-2′-deoxycytidine and TSA, respectively, in human choriodecidual explants also results in an increase in the basal production of TNF-α but not that of IL-1β. The differential response is unique, and the relative uncoupling of IL-1β and TNF-α responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where upregulation of IL-1β is known to be a causative factor.

scholarly journals Mast Cell β-Tryptase Is Enzymatically Stabilized by DNA

2020 ◽  
Vol 21 (14) ◽  
pp. 5065
Author(s):  
Sultan Alanazi ◽  
Mirjana Grujic ◽  
Maria Lampinen ◽  
Ola Rollman ◽  
Christian P. Sommerhoff ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Enzymatic Activity ◽  
Secretory Granules ◽  
Base Pairs ◽  
Double Stranded Dna ◽  
Nuclear Core ◽  
Anionic Charge ◽  
Core Histones ◽  
Nuclear Events

Tryptase is a tetrameric serine protease located within the secretory granules of mast cells. In the secretory granules, tryptase is stored in complex with negatively charged heparin proteoglycans and it is known that heparin is essential for stabilizing the enzymatic activity of tryptase. However, recent findings suggest that enzymatically active tryptase also can be found in the nucleus of murine mast cells, but it is not known how the enzmatic activity of tryptase is maintained in the nuclear milieu. Here we hypothesized that tryptase, as well as being stabilized by heparin, can be stabilized by DNA, the rationale being that the anionic charge of DNA could potentially substitute for that of heparin to execute this function. Indeed, we showed that double-stranded DNA preserved the enzymatic activity of human β-tryptase with a similar efficiency as heparin. In contrast, single-stranded DNA did not have this capacity. We also demonstrated that DNA fragments down to 400 base pairs have tryptase-stabilizing effects equal to that of intact DNA. Further, we showed that DNA-stabilized tryptase was more efficient in degrading nuclear core histones than heparin-stabilized enzyme. Finally, we demonstrated that tryptase, similar to its nuclear localization in murine mast cells, is found within the nucleus of primary human skin mast cells. Altogether, these finding reveal a hitherto unknown mechanism for the stabilization of mast cell tryptase, and these findings can have an important impact on our understanding of how tryptase regulates nuclear events.

scholarly journals Tryptase Regulates the Epigenetic Modification of Core Histones in Mast Cell Leukemia Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Sultan Alanazi ◽  
Fabio Rabelo Melo ◽  
Gunnar Pejler
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
Mast Cells ◽  
Epigenetic Modification ◽  
Secretory Granules ◽  
Leukemia Cells ◽  
Human Mast Cell ◽  
Cell Leukemia ◽  
Core Histones ◽  
Mast Cell Leukemia

Mast cells are immune cells that store large amounts of mast cell-restricted proteases in their secretory granules, including tryptase, chymase and carboxypeptidase A3. In mouse mast cells, it has been shown that tryptase, in addition to its canonical location in secretory granules, can be found in the nuclear compartment where it can impact on core histones. Here we asked whether tryptase can execute core histone processing in human mast cell leukemia cells, and whether tryptase thereby can affect the epigenetic modification of core histones. Our findings reveal that triggering of cell death in HMC-1 mast cell leukemia cells is associated with extensive cleavage of core histone 3 (H3) and more restricted cleavage of H2B. Tryptase inhibition caused a complete blockade of such processing. Our data also show that HMC-1 cell death was associated with a major reduction of several epigenetic histone marks, including H3 lysine-4-mono-methylation (H3K4me1), H3K9me2, H3 serine-10-phosphorylation (H3S10p) and H2B lysine-16-acetylation (H2BK16ac), and that tryptase inhibition reverses the effect of cell death on these epigenetic marks. Further, we show that tryptase is present in the nucleus of both viable and dying mast cell leukemia cells. In line with a role for tryptase in regulating nuclear events, tryptase inhibition caused increased proliferation of the mast cell leukemia cells. Altogether, the present study emphasizes a novel principle for how epigenetic modification of core histones is regulated, and provides novel insight into the biological function of human mast cell tryptase.

The roles of mast cells and Kupffer cells in rat systemic anaphylaxis

2007 ◽  
Vol 293 (6) ◽  
pp. R2202-R2209 ◽  
Author(s):  
Toshishige Shibamoto ◽  
Tomohiro Shimo ◽  
Sen Cui ◽  
Wei Zhang ◽  
Hiromichi Takano ◽  
...  
Keyword(s):  
Mast Cells ◽  
Kupffer Cells ◽  
Early Stage ◽  
Venous Pressure ◽  
Gadolinium Chloride ◽  
Perfused Liver ◽  
Wild Type ◽  
Sprague Dawley ◽  
Systemic Anaphylaxis ◽  
Sprague Dawley Rats

Mast cells and other cells such as macrophages have been shown to mediate systemic anaphylaxis. We determined the roles of mast cells and Kupffer cells in hepatic and systemic anaphylaxis of rats. Roles of mast cells were examined by using the mast cell-deficient white spotting (Ws/Ws) rat; the Ws/Ws and wild type (+/+) rats were sensitized with ovalbumin (1 mg). Roles of Kupffer cells were examined by depleting Kupffer cells using gadolinium chloride or liposome-encapsulated dichloromethylene diphosphonate in the Ws/Ws and Sprague-Dawley rats. An intravenous injection of 0.6 mg ovalbumin caused substantial anaphylactic hypotension in both the Ws/Ws and +/+ rats; however, the occurrence was delayed in the Ws/Ws rats. After antigen, portal venous pressure increased by 13.1 cmH2O in the +/+ rats, while it increased only by 5.7 cmH2O in the Ws/Ws rats. In response to antigen, the isolated perfused liver of the Ws/Ws rats also showed weak venoconstriction, the magnitude of which was one tenth as large as that of the +/+ rats, indicating that hepatic anaphylaxis was primarily due to mast cells. In contrast, Kupffer cell depletion did not attenuate anaphylactic hepatic venoconstriction in isolated perfused livers. In conclusion, mast cells are involved mainly in anaphylactic hepatic presinusoidal portal venoconstriction but only in the early stage of anaphylactic systemic hypotension in rats. Macrophages, including Kupffer cells, do not participate in rat hepatic anaphylactic venoconstriction.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma

2018 ◽  
Vol 25 (2) ◽  
pp. 145-162 ◽  
Author(s):  
Sara Molatore ◽  
Andrea Kügler ◽  
Martin Irmler ◽  
Tobias Wiedemann ◽  
Frauke Neff ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Early Stage ◽  
Pituitary Tumors ◽  
Transcriptome Profiling ◽  
Thyroid Neoplasms ◽  
Recessive Trait ◽  
Wild Type ◽  
Incurable Cancer ◽  
Medullary Thyroid ◽  
Adrenal Pheochromocytoma

Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposingCdkn1bmutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild-typeCdkn1ballele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

2007 ◽  
Vol 293 (2) ◽  
pp. R707-R713 ◽  
Author(s):  
Sharyn M. Fitzgerald ◽  
Barbara K. Kemp-Harper ◽  
Helena C. Parkington ◽  
Geoffrey A. Head ◽  
Roger G. Evans
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Pressure ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
No Production ◽  
Wild Type ◽  
Early Diabetes ◽  
Diabetes In Mice ◽  
Vehicle Treatment

We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of Nω-nitro-l-arginine methyl ester (l-NAME; 100 mg·kg−1·day−1 in drinking water; 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered; the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

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