Activation of TLR2 and TLR4 by minimally modified low-density lipoprotein in human macrophages and monocytes triggers the inflammatory response

Oxidized low-density lipoproteins and Toll-like receptors (TLR) 2 and 4 are involved in the development of atherosclerosis. The TLR are important in the pro-inflammatory response. The aim of this research was to analyze the activation of CD14, TLR4, and TLR2 in response to minimally modified low-density lipoprotein (mmLDL). Human monocytes and macrophages secreted tumor necrosis factor (TNF)–α in response to mmLDL, and blocking CD14 or TLR4 resulted in a ∼60% decrease in mmLDL-induced TNF-α secretion. We also observed similar inhibition of TNF-α synthesis in human monocytes (∼65%) and macrophages (∼70%) when both receptors were blocked simultaneously. When TLR2 was blocked, TNF-α synthesis was inhibited by ∼70% in both cell types. Moreover mmLDL induced redistribution of CD14, TLR4, and TLR2 on the cell surface. This is the first evidence that TLR2 and TLR4 are upregulated in response to mmLDL. Our results suggest that mmLDL activates CD14, TLR4, and TLR2, inducing the production of TNF-α and increasing the expression of TLR2 and TLR4.