MEHP induces pyroptosis and autophagy alternation by cathepsin B activation in INS-1 cells.

Mono-(2-ethylhexyl) phthalate (MEHP) is a primary metabolite of di-(2-ethyl hexyl) phthalate (DEHP) in the organism, which is a major component of plasticizers used worldwide. Exposure to DEHP causes pancreatic beta-cell (INS-1 cells) dysfunction, which is associated with insulin resistance and type 2 diabetes. The present study shows that MEHP decreases the cell viability of INS-1 cells in a concentration-dependent manner and induces pyroptosis at 400 μM. Furthermore, the 400 μM MEHP causes increased lysosomal membrane permeability and cathepsin B (CTSB) release, resulting in NLRP3 activation and pyroptosis. Additionally, low concentration of MEHP (50-200 μM) induces upregulation of autophagy, while 400 μM MEHP reduces autophagy level in INS-1 cells via altering mTORC1 phosphorylation. Surprisingly, CTSB contributes to mTORC1 activation in INS-1 cells treated with 400 μM MEHP. Furthermore, autophagy can alleviate inflammatory response by reducing CTSB activation in MEHP-treated INS-1 cells. These results indicate that exposure to MEHP induces pyroptosis and upregulates autophagy levels in a CTSB-dependent manner, and autophagy plays an essential role in pyroptosis onset in INS-1 cells. Our findings provide a new perspective of the connection between CTSB and autophagy. © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

Lijie Jiang, Tianming Qiu, Xiaofeng Yao, Huangben Chen, Kun Yao, Xiance Sun, Guang Yang, Liping Jiang, Cong Zhang, Ningning Wang, Hongying Zhang, Xiaofang Liu. MEHP induces pyroptosis and autophagy alternation by cathepsin B activation in INS-1 cells. Environmental science and pollution research international. 2021 Dec;28(47):66628-66642

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PMID: 34235687

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