Lysophosphatidic Acid Promotes Expression and Activation of Matrix Metalloproteinase 9 (MMP9) in THP-1 Cells via Toll-Like Receptor 4/Nuclear Factor-κB (TLR4/NF-κB) Signaling Pathway

Abstract

BackgroundLysophosphatidic acid (LPA) is an active compound of oxidized low-density lipoprotein that serves as an endogenous TLR4 ligand. Ligand activation of TLR4 activates nuclear factor-kappaB (NF-κB) and the transcription of NF-κB-regulated inflammatory cytokines, which are involved in the development of atherosclerosis. MMP9 is a member of the MMP family and can affect plaque stability. However, the mechanism responsible for the effect of LPA on the expression and activation of MMP9 has not been fully elucidated. In the present study we examined the effect of LPA on MMP9 expression and activity in THP-1 cells and the involvement of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway in this effect.Material/MethodsHuman THP-1 cells were treated with 0–10 μM LPA for 4 h, or treated with 1 μM LPA for 0–8 h, and were then transfected with TLR4-specific siRNA or treated with 20 μg/ml cafestol acid phenethyl ester (CAPE, an NF-κB inhibitor). MMP9 mRNA and protein levels were measured by quantitative RT-PCR and Western blot analysis, respectively, and MMP9 activity was measured by zymography.ResultsLPA upregulated MMP9 mRNA and protein levels and MMP9 activity in THP-1 cells in both concentration- and time-dependent manners. Transfection of cells with TLR4-siRNA-2 or treatment with CAPE significantly inhibited the upregulated MMP9 expression and activation. This inhibition was further enhanced by combining the TLR4-siRNA-2 transfection and CAPE pretreatment.ConclusionsLPA can promote MMP9 expression and enhance MMP9 activity in THP-1 cells, in part via the TLR4/NF-κB signaling pathway.

An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System

“…It may well be that LPA and not LPC is responsible for the reported effects of LPC and ox-LDL on the development of atherosclerosis. [ 171 , 172 , 173 , 174 , 175 ]. Small molecule inhibitors of autotaxin, a secreted phosphodiesterase that produces LPA from LPC, and thus increasing LPC levels - are a new promising therapeutic option.…”

Increasing the low lipid phosphate phosphatase 1 activity in breast cancer cells decreases transcription by AP-1 and expressions of matrix metalloproteinases and cyclin D1/D3

“…Little is known about whether LPP1 affects the expressions of MMPs in breast cancer. Several studies reported that LPA increases the expression of MMP-2 or MMP-9 in leukemic monocytes 32, neuroblastoma 33, hepatocellular carcinoma cells 34, and ovarian cancer cells 35. This suggests that the low LPP1 activity in cancers could increase MMP levels through the concomitant elevation in LPA signaling.…”

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

“…However, in cells that have not been activated by lipopolysaccharide or other methods of stimulation, baseline levels of cytokines in the media are often too low to be detected [138], [395], [397]. Therefore, while it's possible that increased proinflammatory factors in the conditioned ~ 90 ~ media from apoE2-TR mixed glial cultures, such as increased NFκB levels, is impacting MMP-9 conversion levels [353], [373], [374], they are often in such low abundance in the extracellular media under non-stimulated conditions that their potential influence is likely negligible [138], [395], [397].…”

“…Several activators of MMP-9 have been identified including MMP-2 [230], MMP-3 [231], MMP-7 [232], MMP-10 [233], MMP-13 [234], and the serine protease trypsin [235]. Increased MMP-9 activation is seen following inflammation [200], [372], for instance NF-κB signalling in human endothelial cells has been shown to affect the activation of MMP-9 [353], [373], [374]. MMP-9 is typically processed into the well-established 82-kDa active species, in some instances via an inactive 86 kDa intermediate form [231], [369], [375].…”