A new perspective of triptolide-associated hepatotoxicity: the relevance of NF- B and NF- B-mediated cellular FLICE-inhibitory protein.
10.1016/j.apsb.2020.02.009
- Author:
Ziqiao YUAN
1
;
Zihang YUAN
1
;
Muhammad HASNAT
1
;
Haoran ZHANG
1
;
Peishi LIANG
2
;
Lixin SUN
1
;
Zhenzhou JIANG
1
;
Luyong ZHANG
1
Author Information
1. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
2. College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
- Publication Type:Journal Article
- Keywords:
CIAPs, cellular inhibitor of apoptosis proteins;
Etan, etanercept;
FADD, FAS-associated protein with death domain;
FLIP;
FLIP, cellular FLICE-inhibitory protein;
IκB-α, NF-κB inhibitor alpha;
LDH, lactate dehydrogenase;
LPS;
LPS, lipopolysaccharide;
MLKL, mixed lineage kinase domain like pseudokinase;
MPO, myeloperoxidase;
NF-κB;
PAS, periodic acid-schiff;
RIPK1/3, receptor-interacting protein kinase 1/3;
TNF-R1, tumor necrosis factor receptor type 1;
TNF-α;
TNFAIP3, TNF-α-induced protein 3;
TP, triptolide;
TRADD, TNF receptor-associated death domain;
TRAF2, TNF receptor-associated factor 2;
Triptolide;
XIAP, X-linked inhibitor of apoptosis protein
- From:
Acta Pharmaceutica Sinica B
2020;10(5):861-877
- CountryChina
- Language:English
-
Abstract:
Previously, we proposed a new perspective of triptolide (TP)-associated hepatotoxicity: liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, the mechanisms for TP/LPS-induced hepatotoxicity remained elusive. The present study aimed to clarify the role of LPS in TP/LPS-induced hepatotoxicity and the mechanism by which TP induces liver hypersensitivity upon LPS stimulation. TNF- inhibitor, etanercept, was injected intraperitoneally into mice to investigate whether induction of TNF- by LPS participated in the liver injury induced by TP/LPS co-treatment. Mice and hepatocytes pretreated with TP were stimulated with recombinant TNF- to assess the function of TNF- in TP/LPS co-treatment. Additionally, time-dependent NF-B activation and NF-B-mediated pro-survival signals were measured and . Finally, overexpression of cellular FLICE-inhibitory protein (FLIP), the most potent NF-B-mediated pro-survival protein, was measured and to assess its function in TP/LPS-induced hepatotoxicity. Etanercept counteracted the toxic reactions induced by TP/LPS. TP-treatment sensitized mice and hepatocytes to TNF-, revealing the role of TNF- in TP/LPS-induced hepatotoxicity. Mechanistic studies revealed that TP inhibited NF-B dependent pro-survival signals, especially FLIP, induced by LPS/TNF-. Moreover, overexpression of FLIP alleviated TP/LPS-induced hepatotoxicity and TP/TNF--induced apoptosis . Mice and hepatocytes treated with TP were sensitive to TNF-, which was released from LPS-stimulated immune cells. These and other results show that the TP-induced inhibition of NF-B-dependent transcriptional activity and FLIP production are responsible for liver hypersensitivity.
