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
Views 3468      Downloads 150
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
Article Tools
Follow on us
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.
Macrophage, Cytokines, Cholesterol, Oxysterols, Mevalonate Pathway
To cite this article
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. doi: 10.11648/j.ab.20140201.14
G. Siasos, D. Tousoulis, S. Kioufis, E. Oikonomou, Z. Siasou, M. Limperi et al., "Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases," Curr Top Med Chem, vol. 12, pp. 1132-48, 2012.
N. Watanabe, and U. Ikeda, "Matrix metalloproteinases and atherosclerosis," Curr Atheroscler Rep, vol. 6, pp. 112-20, Mar 2004.
Y. Sh. Schwartz, M. I. Dushkin, N. I. Komarova, E. V. Vorontsova and I. S. Kuznetsova, "Cholesterol-induced stimulation of postinflammatory liver fibrosis," Bull Exp Biol Med, vol. 145, pp. 692-5, Jun 2008.
G. Poli, F. Biasi, and G. Leonarduzzi, "Oxysterols in the pathogenesis of major chronic diseases," Redox Biol, vol. 1, pp. 125-30, Jan 2013.
G. K. Hansson, A. K. Robertson, and C. Söderberg-Nauclér, "Inflammation and atherosclerosis," Annu Rev Pathol, vol. 1, pp. 297-329, Feb 2006.
M. I. Dushkin, E. I. Vereshchagin, A. Iu. Grebenshchikov, A. F. Safina and Y. Sh. Schwartz, "Effects of hydroxysterols on expression of inflammatory cytokine genes and their level in macrophages tolerant to endotoxin," Bull Exp Biol Med, vol. 127, pp. 71-4, Jan 1999.
K. Sadamatsu, H. Shimokawa, H. Tashiro, T. Seto, H. Kakizoe, and K. Yamamoto, "Different effects of simvastatin and losartan on cytokine levels in coronary artery disease," Am J Cardiovasc Drugs, vol. 6, pp. 169-75, 2006.
E. Porreca, C. Di Febbo, G. Baccante, M. Di Nisio, and F. Cuccurullo, "Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin," J Am Coll Cardiol, vol. 39, pp. 1752-57, Jun 2002.
P. Lefebvre, B. Cariou, F. Lien, F. Kuipers, and B. Staels, "Role of bile acids and bile acid receptors in metabolic regulation," Physiol Rev, vol. 89, pp. 147-91, Jan 2009.
M. I. Dushkin, O. M. Perminova, A. F. Safina, N. N. Vol’skii, and Y. Sh. Schwartz, "Influence of the activation of the immune system cells on the parameters of lipid metabolism in macrophages," Zh Microbiol Epidemiol Immunobiol, no. 6, pp. 52-6, Nov-Dec 2004.
M. C. Englund, A. L. Karlsson, O. Wiklund, G. Bondjers, and B. G. Ohlsson, "25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases a lipopolysaccharide-induced TNF-alpha secretion in macrophages," Atherosclerosis, vol. 158, pp. 61-71, Sep 2001.
B. G. Ohlsson, M. C. Englund, A. L. Karlsson, E. Knutsen, C. Erixon, H. Skribeck, et al., "Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages," J Clin Invest, vol. 88, pp. 78-89, Jul 1996.
S. Siegemund, and K. Sauer, "Balancing pro- and anti-inflammatory TLR4 signaling," Nat Immunol, vol. 13, pp. 1031-3, Nov 2012.
M. L. Huynh, V. A. Fadok, and P. M. Henson, "Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation," J Clin Invest, vol. 109, pp. 41-50, Jan 2002.
J. H. Madenspacher, D. W. Draper, K. A. Smoak, H. Li, G. L. Griffiths, B. T. Suratt, et al., "Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes," J Immunol, vol. 185, pp. 1660-9, Aug 2010.
W. Khovidhunkit, M. S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K.R. Feingold, et al., "Effects of infection and inflammation on lipid and lipoprotein metabolism," J Lipid Res, vol. 45, pp. 1169-96, Jul 2004.
R. A. Memon, I. Shechter, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold, "Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein and mRNA levels in Syrian hamsters," J Lipid Res, vol. 38, pp. 1620-29, Aug 1997.
Mather, X. M. Chen, S. McGinn, M. J. Field, S. Sumual, S. Manqiafico, et al., "High glucose induced endothelial cell growth inhibition is associated with an increase in TGFbeta1 secretion and inhibition of Ras prenylation via suppression of the mevalonate pathway," Int J Biochem Cell Biol, vol. 41, pp. 561-9, Mar 2009.
H. J. Park, and J. B. Galper, "3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate TGF- signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase," Proc Natl Acad Sci USA, vol. 96, pp. 11525-30, Sep 1999.
N. M. Bulus, H. M. Sheng, N. Sizemore, S. M. Oldham, J. V. Barnett, R. J. Coffey et al. "Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling," Neoplasia, vol. 2, pp. 357-64, Jul-Aug 2000.
J. Adnane, F. A. Bizouarn, Z. Chen, J. Ohkanda, A. D. Hamilton, T. Munoz-Antonia, et al. "Inhibition of farnesyltransferase increases TGFbeta type II receptor expression and enhances responsiveness of human cancer cells to TGFbeta," Oncogene, vol. 19, pp. 5525-33, Nov 2000.
J. Adnane, E. Seijo, Z. Chen, F. Bizouarn, M. Leal, S. M. Sebti, et al. "RhoB, not RhoA, represses the transcription of the transforming growth factor  Type II Receptor by a mechanism involving activator protein 1," J Biol Chem, vol. 277, pp. 8500–7, Mar 2002.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186