Hypoxia increases 25-hydroxycholesterol-induced interleukin-8 protein secretion in human macrophages

Hypoxia Regulates Macrophage Functions in Inflammation

“…For example, hypoxia increased macrophage intracellular levels of hydrogen peroxide, which coincided with increased binding of the transcription factor AP-1 to the CXCL8 promoter and concurrent increase in CXCL8 mRNA expression (27), suggesting that AP-1 may be the main hypoxia regulated transcription factor regulating CXCL8 expression in hypoxic macrophages (although hypoxic activation of CXCL8 by C/EBP␤ as well as AP-1 has also been demonstrated) (74). Furthermore, using C/EBP␤-deficient macrophage cell lines and peritoneal macrophages from C/EBP␤ knockout mice, Albina et al (75) showed that arginase-1 up-regulation by hypoxia in macrophages is modulated entirely by C/EBP␤.…”

“…Foam cells isolated from human atherosclerotic tissue displayed elevated levels of CXCL8 release compared with macrophages in culture (25). Furthermore, low-density lipoprotein receptor knockout mice with CXCR2 (one of the receptors for CXCL8)-deficient bone marrow cells show reduced atherosclerosis compared with that seen in wild-type mice (26)), suggesting that CXCL8 contributes to atherosclerotic plaque develop- (27). Thus, it appears that hypoxia-induced secretion of CXCL8 from foam cells may lead to the recruitment of smooth muscle cells and T cells into the atherosclerotic plaques and thus to plaque progression.…”

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

“…When human monocytes, monocyte-derived macrophages (THP-1 cells), and porcine retinal pigment epithelial cells were exposed to a series of different oxysterols (7-ketocholesterol, 7ß-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol, or cholestane-3ß,5α,6ß-triol), all of them had a tendency to stimulate IL-8 production, but 25-hydroxycholesterol was the most potent (15). It is worth noting that in human mononuclear cells isolated by Ficoll-Paque centrifugation, the pro-inflammatory activity of 25-hydroxycholesterol was enhanced in hypoxic conditions, and this oxysterol was also capable of potentiating LPS-induced IL-1ß secretion (51). Moreover, in human promonocytic leukemia cells (U937) and the J774-A1 murine macrophage cell line, a biologically representative oxysterol mixture (7α-hydroxycholesterol (5%), 7ß-hydroxycholesterol (10%), cholesterol α-epoxide (20%), cholesterol ß-epoxide (20%), cholestane-3ß,5α,6ß-triol (9%), 7-ketocholesterol (35%), and 25-hy-A.…”

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

“…NIH-3T3 cells were cultured as recommended by the American Type Culture Collection, and L6 cells were a gift from A. Klip (The Hospital for Sick Children, Toronto, Ontario, Canada) and grown as previously described (65). The cells were incubated at 21% oxygen (normoxia) or 1% oxygen (hypoxia) for 24 hours as previously described (66), prior to real-time quantitative RT-PCR analysis of Vldlr expression.…”