Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells

Abstract

There is evidence that low-density lipoprotein (LDL) is modified by hydrolytic enzymes, and that the product (E-LDL) induces selective production of interleukin 8 (IL-8) in endothelial cells. Since nuclear factor-kappaB (NF-kappaB) is a major regulator of IL-8 transcription, we studied its activation in endothelial cells treated with E-LDL. Unexpectedly, the modified lipoprotein not only failed to activate NF-kappaB, but completely blocked its activation by tumour necrosis factor-alpha (TNF-alpha) in EA.hy926-cells, as assessed by electrophoretic mobility shift assays and immunofluorescence. Inhibition occurred upstream of NF-kappaB translocation, as inhibitor of NF-kappaB- (IkappaB)-phosphorylation was suppressed by E-LDL. In contrast to NF-kappaB, transcription factor activator protein-1 (AP-1) proved to be activated. Removal of free fatty acids present in E-LDL obliterated both activation of AP-1 and inhibition of NF-kappaB. Chromatin immunoprecipitation revealed that phosphorylated c-jun, but not NF-kappaBp65 bound to the natural IL-8 promoter. Production of endothelial IL-8 and simultaneous modulation of NF-kappaB in response to hydrolyzed LDL might serve to protect the vessel wall and promote silent removal of the insudated lipoprotein.

Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL‐stimulated human monocytes: implications for atherosclerosis

“…Next, although Fenske et al . (36) reported that SB203580 does not block IL‐8 production by endothelial cells in response to eLDL, suggesting that p38 activation and IL‐8 up‐regulation observed in endothelial cells exposed to eLDL are not causally related, Hakala et al . (12) reported that p38 MAPK was crucial for the hydrolase‐modified LDL‐induced IL‐8 secretion from macrophages.…”

“…Thus, although eLDL has been shown to induce secretion of IL-8 by endothelial cells (10) but not macrophages (22), hydrolase-modified LDL, an LDL modification resembling eLDL, induced substantial secretion of IL-8 by human monocyte-derived macrophages (12). Next, although Fenske et al (36) reported that SB203580 does not block IL-8 production by endothelial cells in response to eLDL, suggesting that p38 activation and IL-8 upregulation observed in endothelial cells exposed to eLDL are not causally related, Hakala et al (12) reported that p38 MAPK was crucial for the hydrolase-modified LDLinduced IL-8 secretion from macrophages. Of course, these discrepancies may be attributable to the different cell lines used.…”

“…Among the wide‐ranging downstream activities of phosphorylated p38 MAPK, cytokine production is a decisive component related to atherosclerosis (35). It has been reported that eLDL modulates inflammatory responses in endothelial cells by selective induction of IL‐8 in endothelial cells (10, 36). In the first instance, we investigated whether eLDL uptake by THP‐1 cells induces cytokines known to be regulated by p38 MAPK.…”

Enzymatically modified LDL atherosclerosis and beyond paving the way to acceptance

“…eLDL is thus able to promote the selective adhesion of monocytes and T lymphocytes to the endothelium, stimulate transmigration of these cells, and foster their retention in the vessel wall by increasing their adherence to SMCs (44). Likewise, production of IL-8 (interleukin-8) and simultaneous modulation of NF-kappaB in response to eLDL might also serve to protect the vessel wall and promote silent removal of the insudated lipoprotein (45).…”

C reactive protein and enzymatically modified LDL cooperatively promote dendritic cell-mediated T cell activation

“…ELDL played multifaceted roles in atherosclerosis. ELDL modulated endothelial inflammatory responses by promoting interleukin 8 production and secretion through activation of transcription factor activator protein-1 [12,32]. Upon binding to C1q, eLDL triggered the classical pathway of complement in a CRP-dependent and -independent fashion [33,34], which contributed to pathological process of atherosclerosis.…”