Methylisothiazolinone induces apoptotic cell death via matrix metalloproteinase activation in human bronchial epithelial cells.

Methylisothiazolinone (MIT) has been used in wide spectrum of fields due to its ability to inhibit microbial proliferation with low toxicity. Meanwhile, in Korea, the concern about the hazardous effects of MIT was amplified by the occurrence of patients that have humidifier disinfectant-associated pulmonary disease. However, the toxic mechanism for the pathological lesion is still unclear. In our previous study, we identified that cell viability decreased more rapidly in bronchial epithelial cells (BEAS-2B cells) compared to keratinocytes and liver epithelial cells under the same exposure condition. In this study we demonstrated that MIT (2, 4 and 8 μg/mL) induced dose-dependent cytotoxicity 24 h after exposure to BEAS-2B cells. Additionally, MIT impaired structure and function of intracellular organelles via oxidative stress, ultimately leading to apoptotic cell death. We also found notable activation of matrix metalloproteinases (MMPs) and clear aggregation of nucleolus proteins in MIT-treated cells. Furthermore, MIT increased secretion of proinflammatory cytokines (Interleukin (IL)-1β, IL-6, and interferon-γ) and a chemokine (IL-8), and microarray and the KEGG pathway analysis proposed possible carcinogenesis following exposure to MIT. Taken together, we conclude that MIT induces apoptotic cell death and inflammatory response by activating MMPs in BEAS-2B cells. We also suggest that further study is necessary to clarify the possible carcinogenesis of MIT.