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.
Highlights
Lymphatic vessels (LVs) are present in most vascularized tissues, and transport fluids, soluble antigens and immune cells
We demonstrated that LPS induces phosphatase 2A (PP2A) activation, which results in the activation of apoptosis signal-regulating kinase 1 (ASK1), p38MAPK and JNK1/2, and subsequent binding of p65 and C/EBPβ to the cox-2 promoter region; together, these culminate in the increased COX-2 expression in LPS-stimulated SV-lymphatic endothelial cells (LECs)
Our results demonstrated that LPS significantly increased COX-2 promoter luciferase activity in cells transfected with wild-type murine COX-2 reporter construct, but this effect was reduced in cells transfected with mutant constructs with C/EBPβ or NF-κB deletion (Fig 1C)
Summary
Lymphatic vessels (LVs) are present in most vascularized tissues, and transport fluids, soluble antigens and immune cells. It is believed that lymphatic vasculature contributes to tissue fluid homeostasis [1, 2], and plays a critical role in modulating inflammatory and immune processes [3]. PP2A Contributed to LPS-Induced COX-2 Expression undergoes substantial changes under pathologic conditions [1, 2]. LPS-elicited inflammatory process is attributed to the expression of cyclooxygenase (COX)-2, which is a key enzyme in prostaglandin biosynthesis and plays a crucial role in inflammationassociated diseases [11]. COX-2 was shown to regulate vascular endothelial functions [12]. Little is known about how LPS regulates COX-2 expression in lymphatic endothelial cells (LECs)
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