The natural pesticide dihydrorotenone induces human plasma cell apoptosis by triggering endoplasmic reticulum stress and activating p38 signaling pathway.
Dihydrorotenone (DHR) is a natural pesticide widely used in farming industry, such as organic produces. DHR is a potent mitochondrial inhibitor and probably induces Parkinsonian syndrome, however, it is not known whether DHR is toxic to other systems. In the present study, we evaluated the cytotoxicity of DHR on human plasma cells. As predicted, DHR impaired mitochondrial function by decreasing mitochondrial membrane potential in plasma cells. Because mito-dysfunction leads to unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, we examined the signature proteins in ER stress, including GRP78, ATF4, and CHOP. After DHR treatment, these proteins were significantly upregulated. It is reported that activation of the mitogen-activated protein kinases p38 and JNK are involved in endoplasmic reticulum stress. However, in the subsequent study, DHR was found to activate p38 but not the JNK signaling. When pre-treated with p38 inhibitor SB203580, activation of p38 and cell apoptosis induced by DHR was partially blocked. Thus, we found that DHR induced human plasma cell death by activating the p38 but not the JNK signaling pathway. Because plasma cells are very important in the immune system, this study provided a new insight in the safety evaluation of DHR application.
Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
Jieyu
J
Zhang
Juan
J
Tang
Biyin
B
Cao
Zubin
Z
Zhang
Jie
J
Li
Aaron D
AD
Schimmer
Sudan
S
He
Xinliang
X
Mao
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D010950:Plasma Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000633:toxicity; D056811:Unfolded Protein Response / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D024101:Mitochondrial Proteins; D010575:Pesticides; D012402:Rotenone; C044985:1',2'-dihydrorotenone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases