title: ZnO nanoparticles induce TNF-α expression via ROS-ERK-Egr-1 pathway in human keratinocytes.
abstract: BACKGROUND
  The area of nanotechnology continues to expand rapidly and zinc oxide (ZnO) nanoparticles (NPs) are widely being used in cosmetics and sunscreens. Although ZnO-NPs are considered materials that can potentially cause skin inflammation, the underlying mechanisms remain elusive.
  
  
  OBJECTIVE
  The aim of this study was to investigate the signaling pathways of a cutaneous inflammatory response induced by ZnO-NPs. ZnO-NPs increased the early growth response-1 (Egr-1) expression, promoter activity and its nuclear translocation in HaCaT cells.
  
  
  METHODS
  HaCaT cells and primary keratinocytes were exposed to ZnO NPs over a range of doses and time course. Protein levels and mRNA levels of Egr-1 and mitogen-activated protein kinase (MAPK) were measured by Western blot and ELISA, respectively. As an in vivo study, ZnO-NPs were applicated on mouse skin, and immunohistochemical stain with TNF-α and Egr-1 was done.
  
  
  RESULTS
  ZnO-NPs activated extracellular signal-regulated kinase (ERK) of MAPK pathways. The up-regulation of Egr-1 expression by ZnO-NPs stimulation was found to be inhibited by an ERK inhibitor, but by neither c-Jun-N-terminal kinase (JNK) nor p38 inhibitor. Antioxidative N-acetyl-cysteine (NAC) strongly inhibited the level of Egr-1 and phosphorylated ERK expression in ZnO-NPs treated cells. ZnO NPs also increased tumor necrosis factor (TNF)-α expression and secretion, which were inhibited by the blockade of Egr-1 expression.
  
  
  CONCLUSIONS
  The present study demonstrated that ZnO-NPs might induce inflammatory response via ROS-ERK-Egr-1 pathway in human keratinocytes.
authors.affiliation: Laboratory of Cell Signaling and Nanomedicine, Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, South Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Jeong
authors.forename: Hee Joo
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Ryu
authors.forename: Woo In
authors.initials: WI
authors.lastname: Ryu
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Park
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Bae
authors.forename: Yeon Sue
authors.initials: YS
authors.lastname: Jang
authors.forename: Sang Wook
authors.initials: SW
authors.lastname: Son
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000633:toxicity*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015034:Zinc Oxide / Q000633:toxicity*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D015034:Zinc Oxide
keywords: ERK; Egr-1; Nanotoxicity; ZnO nanoparticles