Protein Phosphatase 2A in Lipopolysaccharide-Induced Cyclooxygenase-2 Expression in Murine Lymphatic Endothelial Cells

Abstract

The lymphatic endothelium plays an important role in the maintenance of tissue fluid homeostasis. It also participates in the pathogenesis of several inflammatory diseases. However, little is known about the underlying mechanisms by which lymphatic endothelial cell responds to inflammatory stimuli. In this study, we explored the mechanisms by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in murine lymphatic endothelial cells (SV-LECs). LPS caused increases in cox-2 mRNA and protein levels, as well as in COX-2 promoter luciferase activity in SV-LECs. These actions were associated with protein phosphatase 2A (PP2A), apoptosis signal-regulating kinase 1 (ASK1), JNK1/2 and p38MAPK activation, and NF-κB subunit p65 and C/EBPβ phosphorylation. PP2A-ASK1 signaling blockade reduced LPS-induced JNK1/2, p38MAPK, p65 and C/EBPβ phosphorylation. Transfection with PP2A siRNA reduced LPS’s effects on p65 and C/EBPβ binding to the COX-2 promoter region. Transfected with the NF-κB or C/EBPβ site deletion of COX-2 reporter construct also abrogated LPS’s enhancing effect on COX-2 promoter luciferase activity in SV-LECs. Taken together, the induction of COX-2 in SV-LECs exposed to LPS may involve PP2A-ASK1-JNK and/or p38MAPK-NF-κB and/or C/EBPβ cascade.

Quantitative Proteomics Reveals Docosahexaenoic Acid-Mediated Neuroprotective Effects in Lipopolysaccharide-Stimulated Microglial Cells

“…cAMP-regulated phosphoprotein 19 (ARPP19) is an inhibitor for protein phosphatase 2A (PP2A). Previous findings showed LPSs to induce PP2A activation and consequently increased PTGS2 expression in murine lymphatic endothelial cells . LPSs were also found to induce PTGS2 and microsomal PGE2 synthase through the NF-κB pathway and mitogen-activated protein kinases (MAPKs) in cultured astrocytes .…”

“…Previous findings showed LPSs to induce PP2A activation and consequently increased PTGS2 expression in murine lymphatic endothelial cells. 50 LPSs were also found to induce PTGS2 and microsomal PGE2 synthase through the NF-κB pathway and mitogen-activated protein kinases (MAPKs) in cultured astrocytes. 51 Additionally, treatment of rat astrocytes with DHA could negatively regulate prostaglandin synthesis because of the inhibition of PTGS2.…”

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

“…PP2A accounts for about 1% of cellular content within the brain and is the predominant phosphatase that affects tau phosphorylation (80). LPS has been shown to induce PP2A activation in vitro in endothelial cells (81,82). Furthermore, LPS and superoxide, one of the downstream products of LPS-induced inflammation (83), have been shown to induce PP2A activation in hippocampal slices (84,85), indicating that LPS can directly and indirectly induce PP2A activation within the CNS.…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Finally, it is also noteworthy that PP2A inhibition, which also appears to be a universal feature in AD patients [29], may lead to exacerbated PIC production by LPS-activated APCs [136, 137]. The mechanism underpinning this phenomenon has not been fully delineated but it appears to be associated with altered levels of histone post-translational methylation leading to increased transcription of TNFA (the TNF-α gene) and a general increase in inflammatory status [137].…”

“…Finally, it is also noteworthy that PP2A inhibition, which also appears to be a universal feature in AD patients [29], may lead to exacerbated PIC production by LPS-activated APCs [136, 137]. The mechanism underpinning this phenomenon has not been fully delineated but it appears to be associated with altered levels of histone post-translational methylation leading to increased transcription of TNFA (the TNF-α gene) and a general increase in inflammatory status [137]. These findings, allied to those discussed above, may well be important from the perspective of AD pathogenesis as the association between peripherally increased PICs and TREM-2 and increased AD risk and/or severity could be explained by the initiation and/or exacerbation of microglial activation, either as a result of high peripheral PIC levels and/or the egress of activated Th1 and/or Th17 cells into the CNS.…”