Eotaxin-2 is a potent
chemoattractant. High concentration of
eotaxin-2 triggers the
inflammation and
tumor metastasis. Inhibition of
eotaxin-2 may protect experimental
atherogenesis although the mechanism is still unclear.
Toll-like receptor 4 (TLR4) plays a major role mediating vascular
inflammation, which is related to
atherogenesis. In the results, we demonstrated that
eotaxin-2 potentially impairs the tube formation capacity of human coronary artery endothelial cells (HCAECs).
Eotaxin-2 augments the monocytic adhesion in
lipopolysaccharides (LPS)-induced HCAECs, and which were reversed by TLR4
siRNA. Thus this study was conducted to investigate whether
eotaxin-2 increases TLR4 expression, and then enhances the sensitivity of cells to
antigen stimulation in HCAECs, which mediates the increasing of the development of serious
atherosclerosis. In fact, we showed that JNK/SAPK,
p38 MAPK, and ERK1/2 activation contribute to the transcriptional signaling pathway, JNK/SAPK and
p38 MAPK regulate post-transcriptional modification, as well as protein-trafficking pathway in eotaxin-2-treated HCAECs TLR4 expression.
RNA binding proteins, such as human
antigen R (HuR) and
tristetraprolin (
TTP) mediate stability of TLR4
mRNA and chaperone, such as PRAT4A (a
protein associated with TLR4) regulate trafficking of TLR4
protein might confer
eotaxin-2 responsiveness.
Eotaxin-2 administration led to a significant elevation of high
cholesterol diet-induced
atherosclerosis, and of TLR4 expression in B6.129S7-Ldlrtm1Her /J but not Ldlr-/--/-/Tlr4-/- mice. Our results revealed that
eotaxin-2 induced overexpression TLR4 via
mitogen-activated protein kinases (MAPK) signaling pathways,
RNA binding proteins-mediated
mRNA stabilization, and PRAT4A-regulated trafficking in HCAECs. These effects may lead to amplification of inflammatory responses contribute to the pathogenesis of cardiovascular disorders.