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Zinc Oxide Nanoparticles Demoted MDM2 Expression to Suppress TSLP-Induced Mast Cell Proliferation
Abstract:
Activation of murine double minute 2 (MDM2) through thymic stromal lymphopoietin (TSLP)-induced signal transducers and activators of transcription (STAT6) phosphorylation plays a critical role in proliferation and survival of mast cells. Previously, we reported that zinc oxide nanoparticles (ZnO-NP) effectively decrease the mast cell-mediated allergic inflammatory reactions. Here, we evaluated the effect of ZnO-NP on TSLP-induced proliferation of mast cells. ZnO-NP significantly reduced the number of BrdU-incorporating mast cells increased by TSLP. ZnO-NP decreased the expression of MDM2 through the blockade of STAT6 phosphorylation. TSLP increased the production and mRNA expression of interleukin-13 (a growth factor of mast cells), its increase was significantly decreased by ZnO-NP (10 μg/mL). ZnO-NP induced the down-regulation of Bcl2 (an anti-apoptotic factor) and up-regulation of Bax (an apoptotic factor) through the stabilization of p53 protein. However, ZnO-NP has no effect on caspase-3 activation, cytochrome c release into cytosol, and apoptosis-inducing factor translocation into nucleus in TSLP-stimulated cells. The results of the present study demonstrated that ZnO-NP inhibited the proliferation of mast cells through the regulation of MDM2 and p53 protein levels. These finding suggest that ZnO-NP could be improved mast cell-mediated various diseases.
Insights
Zinc oxide nanoparticles (ZnO-NP) inhibit mast cell proliferation by regulating MDM2 and p53 protein levels. These findings suggest ZnO-NP may improve mast cell-mediated diseases.
Area of Science:
- Immunology
- Nanotechnology
- Cell Biology
Background:
- Thymic stromal lymphopoietin (TSLP) signaling, involving signal transducers and activators of transcription 6 (STAT6) phosphorylation, activates murine double minute 2 (MDM2) and promotes mast cell proliferation and survival.
- Zinc oxide nanoparticles (ZnO-NP) have previously shown efficacy in reducing mast cell-mediated allergic inflammatory reactions.
Purpose of the Study:
- To investigate the effect of ZnO-NP on TSLP-induced mast cell proliferation.
- To elucidate the molecular mechanisms underlying ZnO-NP's action on mast cells.
Main Methods:
- Assessing BrdU incorporation to quantify mast cell proliferation.
- Measuring MDM2 expression and STAT6 phosphorylation.
- Quantifying interleukin-13 (IL-13) production and mRNA levels.
- Analyzing Bcl2, Bax, p53 protein levels, caspase-3 activation, cytochrome c release, and apoptosis-inducing factor translocation.
Main Results:
- ZnO-NP significantly reduced TSLP-induced mast cell proliferation.
- ZnO-NP decreased MDM2 expression by blocking STAT6 phosphorylation.
- ZnO-NP attenuated TSLP-induced interleukin-13 production.
- ZnO-NP modulated apoptosis-related proteins (down-regulated Bcl2, up-regulated Bax) via p53 stabilization, without inducing classical apoptosis pathways.
Conclusions:
- ZnO-NP inhibits mast cell proliferation through the regulation of MDM2 and p53 protein levels.
- These findings indicate that ZnO-NP holds potential for therapeutic applications in mast cell-mediated diseases.
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