title: Sintered indium-tin oxide particles induce pro-inflammatory responses in vitro, in part through inflammasome activation.
abstract: Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1β, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1β release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.
authors: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Melissa A
authors: MA
authors: Badding
authors: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Diane
authors: D
authors: Schwegler-Berry
authors: Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Ju-Hyeong
authors: JH
authors: Park
authors: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Natalie R
authors: NR
authors: Fix
authors: Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Kristin J
authors: KJ
authors: Cummings
authors: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, United States of America.
authors: Stephen S
authors: SS
authors: Leonard
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002617:Chemical Industry; D004731:Endotoxins / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016273:Occupational Exposure; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D015398:Signal Transduction; D017971:Tin Compounds / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D004731:Endotoxins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017971:Tin Compounds; D014409:Tumor Necrosis Factor-alpha; C109984:indium tin oxide