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

Abstract

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-αinduced 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 Ca 2+ /CAMK II/ERK/NF-κB signaling pathway; co-treatment with inhibitors of CaMK II (KN93), ERK (LY3214996), NF-κB (PDTC) or Ca 2+ 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 Ca 2+ /CAMKII/ERK/NF-κB signaling pathway. TNF-αimpaired BBB integrity could be reversed by propofol, and propofol attenuates the inhibitory effect of TNF-α on collagen IV.

Exogenous activation of cannabinoid-2 receptor modulates TLR4/MMP9 expression in a spinal cord ischemia reperfusion rat model

“…The myeloid differentiation factor 88 (MyD88) is the central adaptor protein of TLR4 signal pathway, and facilitates the transduction of downstream signaling molecules, such as NF-κB, to regulate the expression of proinflammatory cytokines and chemokines [43][44][45]. In addition, it has been suggested that the activation of MMP9 is modulated by NF-κB phosphorylation [28,46]. To confirm that the exogenous activation of CB2R in the context of I/R injury directly inhibit TLR4 signaling to modulate MMP9 activity, we further analyzed the expression levels of MyD88 and NF-κB phosphorylationin response to the JWH-133 treatment, as well as MMP9 activity by gel zimography.…”

Hypertonic saline mediates the NLRP3/IL‐1β signaling axis in microglia to alleviate ischemic blood‐brain barrier permeability by downregulating astrocyte‐derived VEGF in rats

“…51 It is well documented that activated microglia secrete an array of pro-inflammatory cytokines including TNF-α and IL-1β, and both are involved in disruption of BBB. [52][53][54][55] However, the lack of other cytokines (ie, TNF-a) being investigated in the present study is a limitation and an area for future research. Of course, our study did not prove the upstream mechanism by which HS inhibits NLRP3 inflammasome activation in ischemic stroke.…”

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…Regarding the MMP-9 gene expression, the promoter region of mmp-9 gene contains response elements for transcription factors including Activator Protein-1, Specificity protein-1 and Nuclear Factor-kappa B (NF-kB), as well as Ets-1 binding sites; this renders MMP-9 inducible by either inflammatory mediators or growth factors, as mentioned ( Figure 1 ) [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 34 , 35 , 36 ].…”

“…Whatever the source of its production, MMP-9 retrieves ECM-bound, sequestered growth factors into a soluble, highly diffusible form [ 65 , 66 ]. The solubilized growth factors, together with inflammatory mediators and additional growth factors released by tumor-infiltrating leukocytes, further stimulate the cells constituting the carcinoma mass to generate additional MMP-9 [ 11 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

“…Indeed, MMP-9 could further favor cell detachment because of its ability to shed the integrin β subunit from the cell surface [ 91 ]. However, most of the anti-adhesive effect of MMP-9 depends on the fact that this enzyme efficiently degrades the pericellular matrix and basement membrane in cooperation with other MMPs and/or additional proteolytic enzymes [ 11 , 18 , 19 , 27 , 28 , 29 ].…”