Zinc oxide nanoparticles (ZO-NPs) are used as antimicrobials, anti-inflammatories, and to treat cancer. However, although ZO-NPs have excellent efficiency and specificity, their cytotoxicity is higher than that of micron-sized zinc oxide. Doping ZO-NPs with aluminum can improve therapeutic efficacy, but the biological effects and mechanisms involved have not been elucidated. Here, we reported the efficacy of aluminum-doped ZO-NP (AZO) on thymic stromal lymphopoietin (TSLP) production and caspase-1 activation in human mast cell line, HMC-1 cells. AZO significantly reduced TSLP levels as well as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α without inducing cytotoxicity. Furthermore, AZO more effectively reduced TSLP, IL-6, IL-8, and TNF-α levels than ZO-NP. The levels of inflammatory cytokine mRNA were also reduced by AZO treatment. AZO blocked production of IL-1β and activations of caspase-1 and nuclear factor-κB by inhibiting IκB kinase β and receptor interacting protein 2. In addition, AZO attenuated phosphorylation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase, c-Jun N-terminal kinases, and p38. These findings provide evidence that AZO improves anti-inflammatory properties and offer a safe and effective potential treatment option.
Aydin SevincBHanleyL. Antibacterial activity of dental composites containing zinc oxide nanoparticles. J Biomed Mater Res B Appl Biomater2010; 94: 22–31.
2.
KimMHSeoJHKimHM. Zinc oxide nanoparticles, a novel candidate for the treatment of allergic inflammatory diseases. Eur J Pharmacol2014; 738: 31–39.
3.
RasmussenJWMartinezELoukaP. Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Deliv2010; 7: 1063–1077.
4.
YamakiKYoshinoS. Comparison of inhibitory activities of zinc oxide ultrafine and fine particulates on IgE-induced mast cell activation. Biometals2009; 22: 1031–1040.
5.
JeongSHKimHJRyuHJ. ZnO nanoparticles induce TNF-α expression via ROS-ERK-Egr-1 pathway in human keratinocytes. J Dermatol Sci2013; 72: 263–273.
6.
BoscoMDMohanasundaramDMDrogemullerCJ. Zinc and zinc transporter regulation in pancreatic islets and the potential role of zinc in islet transplantation. Rev Diabet Stud2010; 7: 263–274.
7.
HanleyCThurberAHannaC. The influences of cell type and ZnO nanoparticle size on immune cell cytotoxicity and cytokine induction. Nanoscale Res Lett2009; 4: 1409–1420.
8.
FrohlichE. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomed2012; 7: 5577–5591.
9.
WilsonWWWadeMMHolmanSC. Status of methods for assessing bacterial cell surface charge properties based on zeta potential measurements. J Microbiol Meth2001; 43: 153–164.
10.
SucheaSChristoulakisMKatsarakisN. Comparative study of zinc oxide and aluminum doped zinc oxide transparent thin films grown by direct current magnetron sputtering. Thin Solid Film2007; 515: 6562–6566.
11.
WangXOuDYinJ. Proteomic analysis reveals altered expression of proteins related to glutathione metabolism and apoptosis in the small intestine of zinc oxide-supplemented piglets. Amino Acid2009; 37: 209–218.
12.
SibilanoRFrossiBPucilloCE. Mast cell activation: a complex interplay of positive and negative signaling pathways. Eur J Immunol2014; 44: 2558–2566.
13.
SalujaRZoltowskaAKetelaarME. IL-33 and Thymic Stromal Lymphopoietin in mast cell functions. Eur J Pharmacol2015. pii (in press). DOI: 10.1016/j.ejphar.2015.04.047.
14.
KashyapMRochmanYSpolskiR. Thymic stromal lymphopoietin is produced by dendritic cells. J Immunol2011; 187: 1207–1211.
15.
MoonPDKimHM. Thymic stromal lymphopoietin is expressed and produced by caspase-1/NF-κB pathway in mast cells. Cytokine2011; 54: 239–243.
16.
RedhuNSGounniAS. Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clin Exp Allergy2012; 42: 994–1005.
17.
HanNRKimHMJeongHJ. The β-sitosterol attenuates atopic dermatitis-like skin lesions through down-regulation of TSLP. Exp Biol Med (Maywood)2014; 239: 454–464.
18.
JeongHJNamSYOhHA. Interleukin-32-induced thymic stromal lymphopoietin plays a critical role in macrophage differentiation through the activation of caspase-1 in vitro. Arthritis Res Ther2012; 14: R259–R259.
19.
SongYHNamSYChoiY. Socioeconomic impact of traditional Korean medicine, Pyeongwee-San (KMP6) as an anti-allergic inflammatory drug. TANG2012; 2: e29–e29.
20.
WahabRSiddiquiMASaquibQ. ZnO nanoparticles induced oxidative stress and apoptosis in HepG2 and MCF-7 cancer cells and their antibacterial activity. Colloids Surf B Biointerfaces2014; 117: 267–276.
21.
KimMHJeongHJ. Zinc oxide nanoparticles suppress LPS-Induced NF-κB activation by inducing A20, a aegative regulator of NF-κB, in RAW 264.7 macrophages. J Nanosci Nanotechnol2015; 15: 6509–6515.
22.
SongMKLeeMYSeoJH. Synthesis of high crystalline al-doped ZnO nanopowers from Al2o3 and ZnO by radio-frequency plasma. J Nanomater2015; 2015: 1–6.
23.
YooNJParkWSKimSY. Nod1, a CARD protein, enhances pro-interleukin-1beta processing through the interaction with pro-caspase-1. Biochem Biophy Res Com2002; 299: 652–658.
24.
NamSYKimHYYoouMS. Anti-inflammatory effects of isoacteoside from Abeliophyllum distichum. Immunopharmacol Immunotoxicol2015; 37: 258–264.
25.
MizunoKMorizaneSTakiguchiT. Dexamethasone but not tacrolimus suppresses TNF-α-induced thymic stromal lymphopoietin expression in lesional keratinocytes of atopic dermatitis model. J Dermatol Sci2015; 80: 45–53.
26.
HanNROhHANamSY. TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6. J Invest Dermatol2014 b; 134: 2521–2530.
27.
JeongHJKooHNNaHJ. Inhibition of TNF-alpha and IL-6 production by Aucubin through blockade of NF-kappaB activation RBL-2H3 mast cells. Cytokine2002; 18: 252–259.
28.
JeongHJShinSYOhHA. IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis. J Pathol2011; 224: 553–563.
29.
GauvreauGMO'ByrnePMBouletLP. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med2014; 370: 2102–2110.
30.
HengBCZhaoXTanEC. Evaluation of the cytotoxic and inflammatory potential of differentially shaped zinc oxide nanoparticles. Arch Toxicol2011; 85: 1517–1528.
31.
PanCHLiuWTBienMY. Effects of size and surface of zinc oxide and aluminum-doped zinc oxide nanoparticles on cell viability inferred by proteomic analyses. Int J Nanomed2014; 9: 3631–3643.
32.
XuMFujitaDKajiwaraS. Contribution of physicochemical characteristics of nano-oxides to cytotoxicity. Biomaterials2010; 31: 8022–8031.
33.
ChusueiCCWuCHMallavarapuS. Cytotoxicity in the age of nano: the role of fourth period transition metal oxide nanoparticle physicochemical properties. Chem Biol Interact2013; 206: 319–326.
34.
SeoJHHongBG. Thermal plasma synthsis of nano-sized powders. Nucl Eng Technol2012; 44: 9–20.
35.
SahuDKannanGMVijayaraghavanR. Size-dependent effect of zinc oxide on toxicity and inflammatory potential of human monocytes. J Toxicol Environ Health A2014; 77: 177–191.
36.
MatsumuraMNagataMNakamuraK. Adjuvant effect of zinc oxide on Th2 but not Th1 immune responses in mice. Immunopharmacol Immunotoxicol2010; 32: 56–62.
37.
ChiangHMXiaQZouX. Nanoscale ZnO induces cytotoxicity and DNA damage in human cell lines and rat primary neuronal cells. J Nanosci Nanotechnol2012; 12: 2126–2135.
38.
HuCHSongZHXiaoK. Zinc oxide influences intestinal integrity, the expressions of genes associated with inflammation and TLR4-myeloid differentiation factor 88 signaling pathways in weanling pigs. Innate Immun2014; 20: 478–486.
39.
OuDLiDCaoY. Dietary supplementation with zinc oxide decreases expression of the stem cell factor in the small intestine of weanling pigs. J Nutr Biochem2007; 8: 820–826.
40.
Oyarzun-AmpueroFABreaJLozaMI. A potential nanomedicine consisting of heparin-loaded polysaccharide nanocarriers for the treatment of asthma. Macromol Biosci2012; 12: 176–183.
41.
PatiRMehtaRKMohantyS. Topical application of zinc oxide nanoparticles reduce bacterial skin infection in mice and exhibit antibacterial activity by inducing oxidative stress response and cell membrane disintegration in macrophages. Nanomedicine2014; 10: 1195–1208.
AkhtarMJAlhadlaqHAAlshamsanA. Aluminum doping tunes band gap energy level as well as oxidative stress-mediated cytotoxicity of ZnO nanoparticles in MCF-7 cells. Sci Rep2015; 5: 13876–13876.
44.
TripathyNHongTKHaKT. Effect of ZnO nanoparticles aggregation on the toxicity in RAW 264.7 murine macrophage. J Hazard Mater2014; 270: 110–117.
45.
LuWSenapatiDWangS. Effect of surface coating on the toxicity of silver nanomaterials on human skin keratinocytes. Chem Phys Lett2010; 487: 92–96.
46.
XiaTKovochichMLiongM. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano2008; 2: 2121–2134.
47.
YamanakaKTanakaMTsutsuiH. Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. J Immunol2000; 165: 997–1003.
