Background. Sirtuin (SIRT) proteins are class I histone deacetylases displaying gene regulatory functions in inflammatory, cancer, and metabolic diseases. These SIRT actions involve the nuclear factor κB and its inhibitor IκB pathway. However, the regulation of SIRT in vivo is still unclear. Material and Methods. In a human endotoxemia model, 20 healthy male subjects received an intravenous bolus of 2？ng/kg body weight Escherichia coli endotoxin (LPS). SIRT expression was investigated in peripheral blood mononuclear cells (PBMC) with qPCR and Western blot before and 3 hours, 6 hours, and 24 hours after LPS challenge. Additionally, SIRT regulation was studied in vitro in cultivated PBMC after incubation with 20？ng/mL LPS. Results. A downregulation by >40% of SIRT1 mRNA was detectable 3 hours after LPS and of SIRT3 mRNA 6 hours after LPS. SIRT3, IκBα, and IκB-β protein expressions were decreased 3 and 6 hours after LPS. SIRT2 mRNA or protein expression did not change following LPS. These findings were consistent in vitro and associated with augmented phosphorylation of IκB-β. Discussion. In this E. coli endotoxemia model, SIRT1 and SIRT3 mRNA expressions in PBMC in humans were reduced after LPS challenge. This suggests that SIRT may represent an inflammatory target protein in vivo. 1. Background Nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin, is an enzyme in humans that catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, which is required in the biosynthesis of nicotinamide adenine dinucleotide ( ). As a pivotal component of an salvage pathway, Nampt is also a regulator of the activity of -dependent enzymes, such as class III histone/protein deacetylases (HDAC). Within this group are Sirtuin proteins, of which seven isoforms (SIRT1–7) have so far been identified in humans. Sirtuins possess a wide range of regulatory functions and are implicated in inflammatory diseases, cancer, and aging [1]. The founding Sirtuin member, SIRT1, is associated with stress resistance, metabolism, apoptosis, senescence, differentiation, and aging [1] by directly regulating gene expression through its epigenetic activity on histones and gene silencing [2]. SIRT2, a tubulin deacetylase, functions as a mitotic checkpoint protein [3] and mediates mitotic cell death in response to DNA damage [4]. Recently, it has also been shown that SIRT1 and SIRT2 exert anti-inflammatory effects by deacetylating the RelA/p65 subunit of nuclear factor κB
References
[1]
S. Michan and D. Sinclair, “Sirtuins in mammals: insights into their biological function,” Biochemical Journal, vol. 404, no. 1, pp. 1–13, 2007.
[2]
J. N. Feige and J. Auwerx, “Transcriptional targets of sirtuins in the coordination of mammalian physiology,” Current Opinion in Cell Biology, vol. 20, no. 3, pp. 303–309, 2008.
[3]
T. Inoue, M. Hiratsuka, M. Osaki et al., “SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress,” Oncogene, vol. 26, no. 7, pp. 945–957, 2007.
[4]
N. Matsushita, Y. Takami, M. Kimura et al., “Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells,” Genes to Cells, vol. 10, no. 4, pp. 321–332, 2005.
[5]
A. Csiszar, N. Labinskyy, A. Podlutsky et al., “Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 294, no. 6, pp. H2721–H2735, 2008.
[6]
S. R. Yang, J. Wright, M. Bauter, K. Seweryniak, A. Kode, and I. Rahman, “Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 292, no. 2, pp. L567–L576, 2007.
[7]
F. Yeung, J. E. Hoberg, C. S. Ramsey et al., “Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase,” The EMBO Journal, vol. 23, no. 12, pp. 2369–2380, 2004.
[8]
K. M. Rothgiesser, S. Erener, S. Waibel, B. Lüscher, and M. O. Hottiger, “SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310,” Journal of Cell Science, vol. 123, no. 24, pp. 4251–4258, 2010.
[9]
Z. Gao and J. Ye, “Inhibition of transcriptional activity of c-JUN by SIRT1,” Biochemical and Biophysical Research Communications, vol. 376, no. 4, pp. 793–796, 2008.
[10]
J. Sequeira, G. Boily, S. Bazinet et al., “SIRT1-null mice develop an autoimmune-like condition,” Experimental Cell Research, vol. 314, no. 16, pp. 3069–3074, 2008.
[11]
H. Yang, W. Zhang, H. Pan, H. G. Feldser, E. Lainez, and C. Miller, “SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity,” PLoS ONE, vol. 7, no. 9, Article ID e46364, 2012.
[12]
T. Koyama, S. Kume, D. Koya et al., “SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells,” Free Radical Biology and Medicine, vol. 51, no. 6, pp. 1258–1267, 2011.
[13]
C. J. Boos, F. B. Mayr, G. Y. H. Lip, and B. Jilma, “Endotoxemia enhances circulating endothelial cells in humans,” Journal of Thrombosis and Haemostasis, vol. 4, no. 11, pp. 2509–2511, 2006.
[14]
H. L. Preas II, A. Jubran, R. W. Vandivier et al., “Effect of endotoxin on ventilation and breath variability: role of cyclooxygenase pathway,” The American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 4, pp. 620–626, 2001.
[15]
J. Pleiner, E. Heere-Ress, H. Langenberger et al., “Adrenoceptor hyporeactivity is responsible for Escherichia coli endotoxin-induced acute vascular dysfunction in humans,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 1, pp. 95–100, 2002.
[16]
J. Pleiner, F. Mittermayer, G. Schaller, R. J. MacAllister, and M. Wolzt, “High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm,” Circulation, vol. 106, no. 12, pp. 1460–1464, 2002.
[17]
S. M. Coyle, S. E. Calvano, and S. F. Lowry, “Gender influences in vivo human responses to endotoxin,” Shock, vol. 26, no. 6, pp. 538–543, 2006.
[18]
S. J. H. van Deventer, H. R. Buller, J. W. T. Cate, L. A. Aarden, C. E. Hack, and A. Sturk, “Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways,” Blood, vol. 76, no. 12, pp. 2520–2526, 1990.
[19]
S. E. Calvano and S. M. Coyle, “Experimental human endotoxemia: a model of the systemic inflammatory response syndrome?” Surgical Infections, vol. 13, no. 5, pp. 293–299, 2012.
[20]
Z. Shen, J. M. Ajmo, C. Q. Rogers et al., “Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 296, no. 5, pp. G1047–G1053, 2009.
[21]
N. V. Gorbunov, B. R. Garrison, D. P. McDaniel, et al., “Adaptive redox response of mesenchymal stromal cells to stimulation with lipopolysaccharide inflammagen: mechanisms of remodeling of tissue barriers in sepsis,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 186795, 16 pages, 2013.
[22]
S. H. Jia, Y. Li, J. Parodo et al., “Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis,” Journal of Clinical Investigation, vol. 113, no. 9, pp. 1318–1327, 2004.
