Abstract
The purpose of our study was to investigate the expression levels of TREM-1 (triggering receptor expressed on myeloid cells-1) in U937 foam cells and determine whether TREM-1 regulates the production of tumor necrosis factor-alpha and interleukin-8 in these cells. Human U937 cells were incubated with phorbol 12-myristate 13-acetate and then oxidized human low-density lipoprotein to induce foam cell formation. Oil red O staining was used to identify the foam cells. The production of IL-8 and TNF-α by U937 foam cells was assayed by enzyme-linked immunosorbent assay. The expression of TREM-1 mRNA in U937 foam cells was detected by reverse transcription-polymerase chain reaction. Moreover, U937 foam cells were transfected by small interfering RNA using Lipofectamine 2000 to knockdown TREM-1. Western blot was performed to assay protein expression of TREM-1 and ELISA was used to examine the effect of TREM-1 knockdown on IL-8 and TNF-α production. PMA and ox-LDL induced U937 cells to form foam cells. The production of TNF-α and IL-8 was found to be significantly elevated in U937 foam cells, concomitant with a significant up-regulation of TREM-1 mRNA. TREM-1 siRNA was able to partially silence the expression of TREM-1 protein and remarkably inhibited TNF-α and IL-8 production in U937 foam cells, suggesting that TREM-1 is a positive regulator of TNF-α and IL-8 production in U937 foam cells. Our finding that TREM-1 controls the production of IL-8 and TNF-α in U937 foam cells defines a potentially critical role of TREM-1 in the pathogenesis of atherosclerosis and implicates TREM-1 as a potential therapeutic target for the disease.
Highlights
Atherosclerosis is a complex, progressive disease that is newly recognized to have a strong inflammatory component [, ]
In the presence of oxidized low-density lipoprotein (ox-LDL), phorbol -myristate -acetate (PMA)-induced macrophage-like cells showed obvious foamy changes as many oil red O-positive lipid droplets were observed in the cytoplasm
We demonstrated that ox-LDL treatment significantly up-regulate the expression of TREM- mRNA in PMA-induced macrophage-like cells, and TREM- knockdown remarkably inhibited oxLDL-induced TNF-α and IL- secretion, suggesting that TREM- is a positive regulator of TNF-α and IL- production in U foam cells
Summary
Atherosclerosis is a complex, progressive disease that is newly recognized to have a strong inflammatory component [ , ]. In the early stage of atherosclerosis, monocytes migrate into the arterial intima and differentiate into macrophages that can take up oxidized low-density lipoprotein (ox-LDL) to stimulate differentiation into foam cells [ , ]. The accumulation of foam cells in the artery wall causes the formation of fatty streak(s), the earliest visible lesion of atherosclerosis [ ]. The uptake of ox-LDL by macrophages results in the production of numerous proinflammatory cytokines that can amplify the inflammatory response and promote the evolution of atheroma [ ]. Interleukin- (IL- ) and tumor necrosis factor-alpha (TNF-α) are two important proatherosclerotic cytokines secreted by ox-LDL-activated macrophages [ ]. Both of these molecules have been found to be up-reg-
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