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The role of PERK and IRE1 signaling pathways in excessive fluoride mediated impairment of lymphocytes in rats' spleen in vivo and in vitro

Wei, Wei, Pang, Shujuan, Fu, Xiaoyan, Tan, Shiwen, wang, Qian, Wang, Shize, Sun, Dianjun
Chemosphere 2019 v.223 pp. 1-11
B-lymphocytes, apoptosis, cell division, fluorides, histology, immunosuppression, immunotoxicity, inositols, protein kinases, proteins, rats, signal transduction, spleen
Fluoride is capable of inducing immunotoxicity, but its molecular mechanisms remain elusive. This study aimed to explore the roles of Protein kinase receptor-like ER kinase (PERK) and inositol requiring enzyme 1 (IRE1) signaling pathways in excessive fluoride-induced immunotoxicity, focusing on the regulatory roles of these two pathways in cell division and apoptosis. Firstly, we assessed the changes in cell division and apoptosis in rats exposed to 0, 50, or 100 mg/L fluoride, and detected the expression of PERK and IRE1 signaling-related proteins in spleen. Additionally, to validate the role of these two pathways, we evaluated the changes in cell division and apoptosis of primary lymphocytes from rat's spleen to 4 mM fluoride after knockdown of PERK and IRE1 in vitro. In vivo results confirmed that fluoride inhibited cell division, promoted the apoptosis and resulted in histological and ultrastructural abnormalities of rat spleen. In addition, fluoride induced activation of the PERK and IRE1 signalings and the associated apoptosis. Moreover, the in vitro results further verified the findings in vivo that fluoride activated these two signalings in B lymphocytes. Importantly, after knockdown of PERK and IRE1 in lymphocytes, the cell division ability was restored, and apoptosis decreased in fluoride-treated lymphocytes; the results correlated well with the expression of PERK and IRE1 signaling-related proteins, thus confirming the pivotal role of these pathways in immunosuppression by excessive fluoride. This study indicates that the mechanisms underlying the deleterious effects of fluoride on immune system are related to activation of the PERK and IRE1 signaling pathways.