Lysophospholipids increase IL-8 and MCP-1 expressions in human umbilical cord vein endothelial cells through an IL-1-dependent mechanism

Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both low-molecular-weight lysophospholipid (LPL) ligands which are recognized by the Edg family of G protein-coupled receptors (GPCRs). In endothelial cells, these two ligands activate Edg receptors resulting in cell proliferation and cell migration. Interleukin-8 (IL-8) is a C-X-C chemokine and acts as a chemoattractant of neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine and functions mainly as a chemoattractant of monocytes/macrophages. Both factors are secreted from endothelial cells and have been implicated in the processes leading to atherosclerosis. We examined the effects of LPLs on the expression of IL-8 and MCP-1, key regulators of leukocyte recruitment in human umbilical cord vein endothelial cells (HUVECs). Work illustrated in this article showed that LPA and S1P enhanced IL-8 and MCP-1 mRNA expressions, and protein secretions in dose- and time-dependent fashions. Maximal mRNA expression appeared at 16 hr post-ligand treatment. Using prior treatments with chemical inhibitors, LPLs enhanced IL-8 and MCP-1 expressions through a Gi-, Rho-, and NFkappaB-dependent mechanism. In a chemotaxis assay system, LPL treatments of endothelial cells enhanced monocyte recruitment through upregulating IL-8 and MCP-1 protein secretions. Pre-incubation with AF12198, an IL-1 receptor antagonist or IL-1 functional blocking antibody both suppressed the enhanced effects elicited by LPLs of IL-8 and MCP-1 mRNA expressions in HUVECs. These results suggest that LPLs released by activated platelets might enhance the IL-8- and MCP-1-dependent chemoattraction of monocytes toward the endothelium through an IL-1-dependent mechanism, which may play an important role in facilitating wound-healing and inflammation processes.

LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells

“…Hence, we wondered whether LPA could stimulate endothelial EAhy926 cells to express these two chemokines. As already demonstrated by Lin et al (17) on primary HUVEC cells, we showed that LPA induces MCP-1 and IL-8 at the mRNA and protein levels in a concentration-and time-dependent manner in EAhy926 cells, a model more and more characterized in several in vitro studies related to the context of cardiovascular diseases (14,18,30). We also observed similar results on primary HUVEC cells.…”

“…The PPAR␥ antagonist GW9662 reduced the chemokine secretion to about 50%. It is well documented that MCP-1 and IL-8 are regulated by AP-1 and NFB, two major transcription factors known to be involved in the inflammatory response, in ovarian cancer cells (11), bronchial epithelial cells (44), or endothelial cells (17). The participation of PPAR␥ in the overexpression of MCP-1 and IL-8 is surprising since PPAR␥ has been claimed to exert anti-inflammatory actions by transrepressing proinflammatory genes.…”

“…It also stimulates endothelial adhesion molecule expression and subsequent monocyte-endothelial interactions, a key process in the onset of the early atherosclerotic lesion (32). Moreover, Lin et al (17) have recently demonstrated that LPA enhanced IL-8 and monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC) through a G i/o -, Rho-and nuclear factor (NF)B-dependent mechanism, favoring endothelial cell-leukocyte interactions through the induction of these two chemokines. But, in vivo, the evolution of the initial atherosclerotic lesion relies on a complex interplay between in particular the endothelial cells acting as a secretory tissue, and monocytes responding to them by transmigration.…”

Lysophosphatidic Acid Receptors LPA 1 and LPA 3 Promote CXCL12-Mediated Smooth Muscle Progenitor Cell Recruitment in Neointima Formation

“…Of note, LPA 1 and LPA 3 are involved in LPA-induced monocyte adhesion to endothelial cells via nuclear factor B-dependent upregulation of CCL2 and interleukin-8. 35,38,39 Although the CXCL12/CXCR4 axis, in contrast to CCL2/CC motif receptor 2, has previously not been shown to affect neointimal macrophage content after vascular injury in apoE Ϫ/Ϫ mice, 5,6,9,40 we found that LPA20:4 induced adhesion of monocytic cells in ex vivo-perfused carotid arteries in a CXCR4-dependent manner. However, inhibition of CXCR2, which is crucial in atherogenic monocyte recruitment, 41 similarly reduced LPA20:4-induced monocyte arrest, which indicates a concerted contribution of CXCR4 and CXCR2 possibly through miscellaneous ligands.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…In particular, LPA is involved in infl ammatory cytokine release, monocyte attraction and adhesion, abnormal endothelial cell behavior, endothelial permeability, and LDL uptake for plaque formation (224)(225)(226)(227)(228). These factors can lead to the excessive macrophage invasion seen in atherosclerosis.…”