Cholesterol-Induced Impact on Murine Macrophage Responsiveness Involves down-Regulation of Mevalonate Pathway
Advances in Biochemistry
Volume 2, Issue 1, February 2014, Pages: 24-28
Received: Feb. 8, 2014;
Published: Mar. 10, 2014
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Yakov Sh. Schwartz, FSBI «Research Institute of Internal and Preventive Medicine», SB RAS, Novosibirsk, Russia
Olga M. Dolganova, FSBI «Research Institute of Internal and Preventive Medicine», SB RAS, Novosibirsk, Russia
Sergey V. Cheresiz, FSBI «Research Institute of Internal and Preventive Medicine», SB RAS, Novosibirsk, Russia;FSEIHPE “National Research Novosibirsk State University”, Novosibirsk, Russia
Free cholesterol (Ch) and its oxidative derivatives, oxysterols, are often accumulated in macrophages during chronic inflammation and atherogenesis. The effects of Ch and oxysterols on the balance of pro- and anti-inflammatory cytokines in inflammatory response and the role of mevalonate pathway in the effects of these sterols are studied poorly. We studied the effects of cholesterol, oxysterols, atorvastatin, and mevalonic acid on the LPS-induced TNF-α, IL-10, and TGF-β1 production in macrophage cell culture. The study was carried out in murine peritoneal macrophages preincubated for 4 h with Ch (5 µg/mL), 25-hydroxycholesterol (25-OH-Ch) (5 µg/mL), 7-keto-Ch (5 µg/mL), farnesol (10 µM), or atorvastatin (5 µmol/mL) in the presence or absence of 1 mM of mevalonate. The cells were further incubated in the presence or absence of E. coli 0111:B4 lipopolysaccharide (LPS) for 24 h, and cytokine concentrations in incubation media were determined. Macrophages preincubation with Ch, 25-OH-Ch, or atorvastatin decreased LPS-induced TNF-α production in cell cultures, while supplementation of preincubation medium with mevalonic acid abrogated the effects of atorvastatin and Ch. The Ch, 25-OH-Ch, 7-keto-Ch and atorvastatin significantly reduced IL-10 production by LPS–stimulated macrophages, while farnesol had no effect. Supplementation of Ch or atorvastatin-containing preincubation medium with mevalonate restored IL-10 production. The TGF-β1 production was significantly enhanced by the presence of Ch or atorvastatin in preincubation medium as compared to the control level in non-treated macrophages, while 25-OH-Ch or farnesol decreased profoundly TGF-β1 production. Mevalonate abrogated the effect of Ch or atorvastatin but not of 25-OH-Ch or farnesol. These results allow to conclude, that Ch is able to promote anti-inflammatory and fibrogenic macrophage response, which is connected, at least in part, with the deficiency of mevalonate pathway intermediates, particularly to the deficiency of farnesol, whereas hydroxysterols produce tolerogenic, but not fibrogenic effect, independently of mevalonate pathway.
Yakov Sh. Schwartz,
Olga M. Dolganova,
Sergey V. Cheresiz,
Cholesterol-Induced Impact on Murine Macrophage Responsiveness Involves down-Regulation of Mevalonate Pathway, Advances in Biochemistry.
Vol. 2, No. 1,
2014, pp. 24-28.
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