Effect of titanium dioxide nanoparticles (TiO2NPs) on the expression of mucin genes in human airway epithelial cells.
Titanium dioxide nanoparticles (TiO2NPs) are utilized with growing frequency for a wide variety of industrial applications. Recently, acute and chronic exposures to TiO2NPs have been found to induce inflammatory response in the human respiratory tract. However, the effect and mechanism underlying the induction of major airway mucins by TiO2NPs have not been elucidated. This study was conducted to characterize the effect of TiO2NPs, and the mechanism involved, on the expressions of airway mucins in human airway epithelial cells.



In NCI-H292 cells and primary cultures of normal nasal epithelial cells, the effects of TiO2NPs and signaling pathway for airway mucin genes were investigated by reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, enzyme immunoassays and immunoblot analysis using several specific inhibitors and small interfering RNAs (siRNAs).



TiO2NPs increased MUC5B expression and activated the phosphorylations of extracellular signal-related kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). U0126 (an ERK1/2 MAPK inhibitor) and SB203580 (a p38 MAPK inhibitor) inhibited TiO2NPs-induced MUC5B expression. And knockdown of ERK1, ERK2 and p38 MAPK using siRNAs significantly blocked TiO2NPs-induced MUC5B mRNA expression. Furthermore, Toll-like receptor 4 (TLR4) mRNA expression was increased by TiO2NPs, and knockdown by TLR4 siRNA significantly attenuated TiO2NPs-induced MUC5B mRNA expression and the TiO2NPs-induced phosphorylations of ERK1/2 and p38 MAPK.



These results demonstrate for the first time that TiO2NPs induce MUC5B expression via TLR4-dependent ERK1/2 and p38 MAPK signaling pathways in respiratory epithelium.
a Graduate School of Health and Welfare, CHA University , Pocheon , Republic of Korea.
Gui Ok
GO
Kim
b Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine , Yeungnam University , Daegu , Republic of Korea.
Yoon Seok
YS
Choi
b Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine , Yeungnam University , Daegu , Republic of Korea.
Chang Hoon
CH
Bae
b Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine , Yeungnam University , Daegu , Republic of Korea.
Si-Youn
SY
Song
b Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine , Yeungnam University , Daegu , Republic of Korea.|c Regional Center for Respiratory Diseases , Yeungnam University Medical Center , Daegu , Republic of Korea.
Yong-Dae
YD
Kim
D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D014025:Titanium / Q000633:toxicity*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D009077:Mucins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009495:titanium dioxide; D014025:Titanium; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases
MUC5B; mitogen-activated protein kinases; nanoparticles; respiratory epithelium; titanium dioxide; toll-like receptor 4