The Korean Journal of Physiology and Pharmacology

  • 제22권4호
  • /
  • Pages.379-389
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  • 2018
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  • 1226-4512(pISSN)
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  • 2093-3827(eISSN)
대한약리학회 (The Korean Society of Pharmacology)
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Adenine attenuates lipopolysaccharide-induced inflammatory reactions

  • Silwal, Prashanta (Department of Medical Science, College of Medicine, Chungnam National University) ;
  • Lim, Kyu (Department of Biochemistry, College of Medicine, Chungnam National University) ;
  • Heo, Jun-Young (Department of Biochemistry, College of Medicine, Chungnam National University) ;
  • Park, Jong IL (Department of Biochemistry, College of Medicine, Chungnam National University) ;
  • Namgung, Uk (Department of Oriental Medicine, Daejeon University) ;
  • Park, Seung-Kiel (Department of Medical Science, College of Medicine, Chungnam National University)
  • 투고 : 2017.09.29
  • 심사 : 2018.04.06
  • 발행 : 2018.07.01
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초록

A nucleobase adenine is a fundamental component of nucleic acids and adenine nucleotides. Various biological roles of adenine have been discovered. It is not produced from degradation of adenine nucleotides in mammals but produced mainly during polyamine synthesis by dividing cells. Anti-inflammatory roles of adenine have been supported in IgE-mediated allergic reactions, immunological functions of lymphocytes and dextran sodium sulfate-induced colitis. However adenine effects on Toll-like receptor 4 (TLR4)-mediated inflammation by lipopolysaccharide (LPS), a cell wall component of Gram negative bacteria, is not examined. Here we investigated anti-inflammatory roles of adenine in LPS-stimulated immune cells, including a macrophage cell line RAW264.7 and bone marrow derived mast cells (BMMCs) and peritoneal cells in mice. In RAW264.7 cells stimulated with LPS, adenine inhibited production of pro-inflammatory cytokines $TNF-{\alpha}$ and IL-6 and inflammatory lipid mediators, prostaglandin $E_2$ and leukotriene $B_4$. Adenine impeded signaling pathways eliciting production of these inflammatory mediators. It suppressed $I{\kappa}B$ phosphorylation, nuclear translocation of nuclear factor ${\kappa}B$ ($NF-{\kappa}B$), phosphorylation of Akt and mitogen activated protein kinases (MAPKs) JNK and ERK. Although adenine raised cellular AMP which could activate AMP-dependent protein kinase (AMPK), the enzyme activity was not enhanced. In BMMCs, adenine inhibited the LPS-induced production of $TNF-{\alpha}$, IL-6 and IL-13 and also hindered phosphorylation of $NF-{\kappa}B$ and Akt. In peritoneal cavity, adenine suppressed the LPS-induced production of $TNF-{\alpha}$ and IL-6 by peritoneal cells in mice. These results show that adenine attenuates the LPS-induced inflammatory reactions.

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참고문헌

  1. Kishi T, Kittaka E, Hyodo S, Kashiwa H, Karakawa T, Suzawa T, Sakura N, Sakano T, Usui T. Inhibition by adenine of in vitro immunological functions of normal and adenine phosphoribosyltransferase-deficient human lymphocytes. Immunopharmacology. 1985;10:157-162. https://doi.org/10.1016/0162-3109(85)90021-9
  2. Hershfield MS, Snyder FF, Seegmiller JE. Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes. Science. 1977;197:1284-1287. https://doi.org/10.1126/science.197600
  3. Watanabe S, Yoshimi Y, Ikekita M. Neuroprotective effect of adenine on purkinje cell survival in rat cerebellar primary cultures. J Neurosci Res. 2003;74:754-759. https://doi.org/10.1002/jnr.10790
  4. Avila MA, Garcia-Trevijano ER, Lu SC, Corrales FJ, Mato JM. Methylthioadenosine. Int J Biochem Cell Biol. 2004;36:2125-2130. https://doi.org/10.1016/j.biocel.2003.11.016
  5. Kamatani N, Carson DA. Dependence of adenine production upon polyamine synthesis in cultured human lymphoblasts. Biochim Biophys Acta. 1981;675:344-350. https://doi.org/10.1016/0304-4165(81)90024-6
  6. Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013;18:556-566. https://doi.org/10.1016/j.cmet.2013.08.019
  7. Bender E, Buist A, Jurzak M, Langlois X, Baggerman G, Verhasselt P, Ercken M, Guo HQ, Wintmolders C, Van den Wyngaert I, Van Oers I, Schoofs L, Luyten W. Characterization of an orphan G proteincoupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. Proc Natl Acad Sci U S A. 2002;99:8573-8578. https://doi.org/10.1073/pnas.122016499
  8. von Kugelgen I, Schiedel AC, Hoffmann K, Alsdorf BB, Abdelrahman A, Muller CE. Cloning and functional expression of a novel Gi protein-coupled receptor for adenine from mouse brain. Mol Pharmacol. 2008;73:469-477.
  9. Wengert M, Adao-Novaes J, Assaife-Lopes N, Leao-Ferreira LR, Caruso-Neves C. Adenine-induced inhibition of Na+-ATPase activity: Evidence for involvement of the Gi protein-coupled receptor in the cAMP signaling pathway. Arch Biochem Biophys. 2007;467:261-267. https://doi.org/10.1016/j.abb.2007.08.018
  10. Simon ER, Chapman RG, Finch CA. Adenine in red cell preservation. J Clin Invest. 1962;41:351-359. https://doi.org/10.1172/JCI104489
  11. Tokuda S, Fukuda T, Kobayashi Y, Tanaka M, Matsui T. Effect of the uncharged imidazolium moiety in adenine on endotheliumindependent relaxation in the contracted thoracic aorta of Sprague-Dawley rats. Biosci Biotechnol Biochem. 2012;76:828-830. https://doi.org/10.1271/bbb.110806
  12. Snyder FF, Hershfield MS, Seegmiller JE. Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts. Cancer Res. 1978;38:2357-2362.
  13. Ito K, Uchino H. Control of pyrimidine biosynthesis in human lymphocytes. Inhibitory effect of guanine and guanosine on induction of enzymes for pyrimidine biosynthesis de novo in phytohemagglutinin- stimulated lymphocytes. J Biol Chem. 1976;251:1427-1430.
  14. Silwal P, Shin K, Choi S, Kang SW, Park JB, Lee HJ, Koo SJ, Chung KH, Namgung U, Lim K, Heo JY, Park JI, Park SK. Adenine suppresses IgE-mediated mast cell activation. Mol Immunol. 2015;65:242-249. https://doi.org/10.1016/j.molimm.2015.01.021
  15. Fukuda T, Majumder K, Zhang H, Turner PV, Matsui T, Mine Y. Adenine inhibits $TNF-{\alpha}$ signaling in intestinal epithelial cells and reduces mucosal inflammation in a dextran sodium sulfate-induced colitis mouse model. J Agric Food Chem. 2016;64:4227-4234. https://doi.org/10.1021/acs.jafc.6b00665
  16. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085-2088. https://doi.org/10.1126/science.282.5396.2085
  17. Savva A, Roger T. Targeting toll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases. Front Immunol. 2013;4:387.
  18. Paterson RL, Webster NR. Sepsis and the systemic inflammatory response syndrome. J R Coll Surg Edinb. 2000;45:178-182.
  19. Herzum I, Renz H. Inflammatory markers in SIRS, sepsis and septic shock. Curr Med Chem. 2008;15:581-587. https://doi.org/10.2174/092986708783769704
  20. De Nardo D. Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine. 2015;74:181-189. https://doi.org/10.1016/j.cyto.2015.02.025
  21. Zhang YL, Dong C. MAP kinases in immune responses. Cell Mol Immunol. 2005;2:20-27.
  22. Schorey JS, Cooper AM. Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell Microbiol. 2003;5:133-142. https://doi.org/10.1046/j.1462-5822.2003.00263.x
  23. O'Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353-364. https://doi.org/10.1038/nri2079
  24. Madrid LV, Mayo MW, Reuther JY, Baldwin AS Jr. Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem. 2001;276:18934-18940. https://doi.org/10.1074/jbc.M101103200
  25. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327:656-661. https://doi.org/10.1126/science.1178331
  26. Ma J, Chen T, Mandelin J, Ceponis A, Miller NE, Hukkanen M, Ma GF, Konttinen YT. Regulation of macrophage activation. Cell Mol Life Sci. 2003;60:2334-2346. https://doi.org/10.1007/s00018-003-3020-0
  27. Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique features. Front Immunol. 2012;3:185.
  28. Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4:787-799. https://doi.org/10.1038/nri1460
  29. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373-384. https://doi.org/10.1038/ni.1863
  30. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871-1875. https://doi.org/10.1126/science.294.5548.1871
  31. Jacobs MD, Harrison SC. Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998;95:749-758. https://doi.org/10.1016/S0092-8674(00)81698-0
  32. Cheng YF, Young GH, Lin JT, Jang HH, Chen CC, Nong JY, Chen PK, Kuo CY, Kao SH, Liang YJ, Chen HM. Activation of AMP-activated protein kinase by adenine alleviates TNF-alpha-induced inflammation in human umbilical vein endothelial cells. PLoS One. 2015;10:e0142283. https://doi.org/10.1371/journal.pone.0142283
  33. Young GH, Lin JT, Cheng YF, Huang CF, Chao CY, Nong JY, Chen PK, Chen HM. Identification of adenine modulating AMPK activation in NIH/3T3 cells by proteomic approach. J Proteomics. 2015;120:204-214. https://doi.org/10.1016/j.jprot.2015.03.012
  34. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis. 1999;179 Suppl 2:S294-304. https://doi.org/10.1086/513856
  35. Leon LR, White AA, Kluger MJ. Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol. 1998;275:R269-277.
  36. Dahdah A, Gautier G, Attout T, Fiore F, Lebourdais E, Msallam R, Daeron M, Monteiro RC, Benhamou M, Charles N, Davoust J, Blank U, Malissen B, Launay P. Mast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosis. J Clin Invest. 2014;124:4577-4589. https://doi.org/10.1172/JCI75212
  37. Ajuebor MN, Das AM, Virag L, Flower RJ, Szabo C, Perretti M. Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J Immunol. 1999;162:1685-1691.
  38. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107:135-142. https://doi.org/10.1172/JCI11914
  39. Karin M. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem. 1999;274:27339-27342. https://doi.org/10.1074/jbc.274.39.27339
  40. Hochdorfer T, Kuhny M, Zorn CN, Hendriks RW, Vanhaesebroeck B, Bohnacker T, Krystal G, Huber M. Activation of the PI3K pathway increases TLR-induced $TNF-{\alpha}$ and IL-6 but reduces IL-$1{\beta}$ production in mast cells. Cell Signal. 2011;23:866-875. https://doi.org/10.1016/j.cellsig.2011.01.012
  41. Kuo CL, Ho FM, Chang MY, Prakash E, Lin WW. Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. J Cell Biochem. 2008;103:931-940. https://doi.org/10.1002/jcb.21466
  42. Jhun BS, Jin Q, Oh YT, Kim SS, Kong Y, Cho YH, Ha J, Baik HH, Kang I. 5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264.7 murine macrophages. Biochem Biophys Res Commun. 2004;318:372-380. https://doi.org/10.1016/j.bbrc.2004.04.035
  43. Thimm D, Schiedel AC, Peti-Peterdi J, Kishore BK, Muller CE. The nucleobase adenine as a signalling molecule in the kidney. Acta Physiol (Oxf). 2015;213:808-818. https://doi.org/10.1111/apha.12452

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