Abstract
Purpose
S-Adenosylmethionine (SAM) is beneficial for lipopolysaccharide (LPS)-induced liver injury, but its molecular basis is not fully understood. The present study was carried out to investigate the effects of SAM on LPS signal transduction and its possible mechanism.
Methods
An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10 mg/kg LPS pretreatment with or without SAM (170 μmol/kg body weight). Toll-like receptor 4 (TLR4) protein expression in liver tissues and the tumor necrosis factor alpha (TNF-α) secretion level in serum were detected by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Then, Kupffer cells (KCs) were isolated and challenged with LPS, with or without SAM pretreatment (1,000 μM), and the expressions of TLR4 and myeloid differentiation primary response protein (MYD88) were assayed at the mRNA and protein levels. The activities of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) were also analyzed using Western blotting.
Results
SAM significantly improved the survival rate of endotoxemic mice (p < 0.05) and decreased TNF-α levels in serum (p < 0.05). Simultaneously, SAM also attenuated LPS-induced liver injury and expression of TLR4 and MYD88 in the hepatic sinusoid. Moreover, TLR4 and MYD88 gene and protein expressions were downregulated by SAM pretreatment in LPS-stimulated KCs. Finally, SAM did not affect NF-κB-p65 translocation into the nucleus (p > 0.05), but significantly inhibited p38 MAPK activation (p < 0.05).
Conclusions
SAM attenuated liver injury and improved the survival rate in endotoxemic mice by decreasing the TNF-α expression. The downregulative effect of SAM on TNF-α was mediated by suppressing activation of the TLR4/MAPK signaling pathway.
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References
Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci 2013;58:2223–2236
Su GL. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 2002;283:G256–G265
Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013;25(496):445–455
Yee SB, Ganey PE, Roth RA. The role of Kupffer cells and TNF-alpha in monocrotaline and bacterial lipopolysaccharide-induced liver injury. Toxicol Sci Off J Soc Toxicol 2003;71:124–132
Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 2009;51:212–223
Lu SC, Mato JM. S-Adenosylmethionine in liver health, injury, and cancer. Physiol Rev 2012;92:1515–1542
Song Z, Barve S, Chen T, et al. S-Adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes. Am J Physiol Gastrointest Liver Physiol 2003;284:G949–G955
Anstee QM, Day CP. S-Adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol 2012;57:1097–1109
Palsson-McDermott EM, O’Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 2004;113:153–162
O’Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 2013;13:453–460
Oliva J, Bardag-Gorce F, Li J, French BA, French SW. S-Adenosylmethionine prevents the up regulation of Toll-like receptor (TLR) signaling caused by chronic ethanol feeding in rats. Exp Mol Pathol 2011;90:239–243
Xu FL, You HB, Li XH, Chen XF, Liu ZJ, Gong JP. Glycine attenuates endotoxin-induced liver injury by downregulating TLR4 signaling in Kupffer cells. Am J Surg 2008;196:139–148
Liu ZJ, Liu XL, Zhao J, et al. The effects of SOCS-1 on liver endotoxin tolerance development induced by a low dose of lipopolysaccharide are related to dampen NF-kappaB-mediated pathway. Dig Liver Dis 2008;40:568–577
Wei S, Huang Q, Li J, et al. Taurine attenuates liver injury by downregulating phosphorylated p38 MAPK of Kupffer cells in rats with severe acute pancreatitis. Inflammation 2012;35:690–701
Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J. qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol 2007;8:R19
Wang HL, Zhang WH, Lei WF, Zhou CQ, Ye T. The inhibitory effect of lidocaine on the release of high mobility group box 1 in lipopolysaccharide-stimulated macrophages. Anesth Analg 2011;112:839–844
Fabre C, Mimura N, Bobb K, et al. Dual inhibition of canonical and noncanonical NF-kappaB pathways demonstrates significant antitumor activities in multiple myeloma. Clinical Cancer Res Off J Am Assoc Cancer Res 2012;1(18):4669–4681
Song Z, Uriarte S, Sahoo R, et al. S-Adenosylmethionine (SAMe) modulates interleukin-10 and interleukin-6, but not TNF, production via the adenosine (A2) receptor. Biochim Biophys Acta 2005;15(1743):205–213
Watson WH, Zhao Y, Chawla RK. S-Adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha. Biochem J 1999;342(Pt 1):21–25
Ara AI, Xia M, Ramani K, Mato JM, Lu SC. S-Adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. Hepatology 2008;47:1655–1666
Chawla RK, Watson WH, Eastin CE, Lee EY, Schmidt J, McClain CJ. S-Adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am J Physiol 1998;275:G125–G129
Shih VF, Tsui R, Caldwell A, Hoffmann A. A single NF-kappaB system for both canonical and non-canonical signaling. Cell Res 2011;21:86–102
Veal N, Hsieh CL, Xiong S, Mato JM, Lu S, Tsukamoto H. Inhibition of lipopolysaccharide-stimulated TNF-alpha promoter activity by S-adenosylmethionine and 5′-methylthioadenosine. Am J Physiol Gastrointest Liver Physiol 2004;287:G352–G362
Ko K, Yang H, Noureddin M, et al. Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia in mice. Lab Investig 2008;88:1121–1129
Gobejishvili L, Avila DV, Barker DF, et al. S-Adenosylmethionine decreases lipopolysaccharide-induced phosphodiesterase 4B2 and attenuates tumor necrosis factor expression via cAMP/protein kinase A pathway. J Pharmacol Exp Ther 2011;337:433–443
Acknowledgements
The authors acknowledge the financial support for this project by the National Natural Science Foundation of China (No. 30500473, 30772098).
Compliance with ethical requirements and Conflict of interest
All institutional and national guidelines for the care and use of laboratory animals were followed. Peizhi Li, Zhao Zhang, Jianping Gong, Yan Zhang and Xiwen Zhu declare that they have no conflict of interest.
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Li, P., Zhang, Z., Gong, J. et al. S-Adenosylmethionine attenuates lipopolysaccharide-induced liver injury by downregulating the Toll-like receptor 4 signal in Kupffer cells. Hepatol Int 8, 275–284 (2014). https://doi.org/10.1007/s12072-014-9528-6
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DOI: https://doi.org/10.1007/s12072-014-9528-6