Oxidized Low-Density Lipoprotein Induces Inflammatory Responses in Cultured Human Mast Cells Via Toll-Like Receptor 4

Abstract

Background/Aims: Oxidized low-density lipoprotein (ox-LDL) is a powerful atherogen. Toll-like receptor 4 (TLR4) has a pathophysiological role in regulating inflammatory responses and atherosclerosis. Mast cells can infiltrate into the atheromatous plaque and secrete various pro-inflammatory cytokines, which significantly amplify the atherogenic processes and promote plaque vulnerability. Small interfering RNA (siRNA) is an effective method to silence the target genes. We evaluated whether ox-LDL-induced inflammation depended in part on the activation of TLR4-dependent signaling pathways in a cultured human mast cell line (HMC-1). Method: HMC-1 cells were cultured, and treated with ox-LDL, TLR4-specific siRNA, or inhibitors of phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear factor-κB (NF-κB), a critical mediator of inflammation. The expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a) and interleukin 6 (IL-6) was measured subsequently. Results: Ox-LDL increased the expression of TLR4 and secretion of MCP-1, TNF-a and IL-6. Moreover, ox-LDL stimulated the translocation of NF-κB, from the cytoplasm to nucleus. Additionally, phosphorylation of MAPK was greatly increased. These ox-LDL-induced alterations were significantly attenuated by pretreatment with TLR4-specific siRNA. Conclusion: Ox-LDL induced inflammatory responses in cultured HMC-1 cells including NF-κB nuclear translocation and phosphorylation of MAPKs, a process mediated in part by TLR4.

Hypercholesterolemia Increases the Production of Leukotriene B4 in Neutrophils by Enhancing the Nuclear Localization of 5-Lipoxygenase

“…Importantly, upregulation of LTB4 is also associated with enhanced phosphorylation, and hence activation, of ERK1/2. These observations suggest a mechanism that is consistent with findings from human and animal studies on the pathology of hypercholesterolemia- induced inflammation [12]. …”

RRx-001: a systemically non-toxic M2-to-M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials

“…In addition, the supernatant of RRx-001-incubated RBCs switched the TAM phenotype from M2 to M1 [19]. It is hypothesized that this switch occurs as a result of the catabolism of the lipid-rich RRx-001-modified red blood cell, since oxidized low-density lipoprotein is known to activate macrophages through the toll-like receptor 4 [27]. These M1 repolarized TAMs, which express proinflammatory cytokines such as tumor necrosis factor alpha, interleukin-6, and interferon gamma, stimulate the adaptive arm of the immune system as demonstrated by the infiltration of CD8 + T cells on patient biopsies.…”

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

“…TLR4 has been demonstrated to mediate myocardial ischemia reperfusion injury, maladaptive left ventricular remodeling and increased infarct size after myocardial infarction[13, 14, 24, 25]. Some research findings suggest that the activation of TLR4 signaling pathway is considered to be a promising therapeutic target for the treatment of atherosclerotic cardiovascular diseases[16, 26, 27]. In the present study, we revealed that the mRNA and protein levels of TLR4 were up-regulated after CME in rats.…”