Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

Xiao-wei Ding1, Xia Sun1, Xue-fang Shen1, Yan Lu1,2, Jia-qiang Wang1, Zhi-rong Sun1, Chang-hong Miao1, Jia-wei Chen1
1 Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2 Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200032, China
Correspondence to: Zhi-rong Sun:, Chang-hong Miao:, Jia-wei Chen:,
DOI: 10.1038/s41401-019-0258-0
Received: 31 January 2019
Accepted: 21 May 2019
Advance online: 24 June 2019


Metalloproteinase 9 (MMP-9) is able to degrade collagen IV, an important component of blood–brain barrier (BBB). Expression of MMPs, especially MMP-9, correlates with BBB disruption during central nervous system inflammation. Propofol has been reported to have anti-inflammation effects. In this study, we investigated the effects of propofol on TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells (hCMEC/D3 cells) and explored the underlying mechanisms. The hCMEC/D3 cells were treated with propofol (25 μM), followed by TNF-α (25 ng/mL). We showed that TNF-α treatment markedly increased MMP-9 expression and decreased collagen IV expression in hCMEC/D3 cells, which was blocked by pretreatment with propofol. TNF-α-induced downregulation of collagen IV was also reversed by MMP-9 knockdown with siRNA. We revealed that TNF-α upregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca2+/CAMK II/ERK/NF-κB signaling pathway; co-treatment with inhibitors of CaMK II (KN93), ERK (LY3214996), NF-κB (PDTC) or Ca2+chelator (BAPTA-AM) abrogated the effect of TNF-α on MMP-9 expression. We further established an in vitro BBB model by co-culturing of hCMEC/D3 cells and human astrocytes for 6 days and measuring trans-endothelial electrical resistance (TEER) to reflect the BBB permeability. TNF-α treatment markedly decreased TEER value, which was attenuated by pretreatment with propofol (25 μM) or MMP-9 knockdown with siRNA. In conclusion, propofol inhibits TNF-α-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca2+/CAMKII/ERK/NF-κB signaling pathway. TNF-α-impaired BBB integrity could be reversed by propofol, and propofol attenuates the inhibitory effect of TNF-α on collagen IV.
Keywords: blood-brain barrier; propofol; TNF-α; MMP-9; hCMEC/D3 cells

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