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Review

Targeting methionine cycle as a potential therapeutic strategy for immune disorders

, , &
Pages 861-877 | Received 14 Apr 2017, Accepted 18 Aug 2017, Published online: 23 Aug 2017

References

  • Deng GM, Tsokos GC. Pathogenesis and targeted treatment of skin injury in SLE. Nat Reviews Rheumatol. 2015;11:663–669.
  • Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nature Review Drug Discov. 2016;15:568–588.
  • Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov. 2006;5:197–209.
  • Croft M, Benedict CA, Ware CF. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov. 2013;12:147–168.
  • Ballestar E. Epigenetic alterations in autoimmune rheumatic diseases. Nat Rev Rheumatol. 2011;7:263–271. Epub 2011/02/24.
  • Long H, Yin H, Wang L, et al. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity. J Autoimmun. 2016;74:118–138.
  • Yuan C-S, Saso Y, Lazarides E, et al. Recent advances in S-adenosyl-L-homocysteine hydrolase inhibitors and their potential clinical applications. Expert Opin Ther Pat. 2005;9:1197–1206.
  • Hannibal L, Blom HJ. Homocysteine and disease: causal associations or epiphenomenons? Mol Aspects Med. 2017;53:36–42.
  • Tardif V, Manenkova Y, Berger M, et al. Critical role of transmethylation in TLR signaling and systemic lupus erythematosus. Clin Immunol. 2013;147:133–143.
  • He SJ, Lin ZM, Wu YW, et al. Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZBxNZW F1 mice via interference with TLR-mediated APC response. Acta Pharmacol Sin. 2014;35:219–229.
  • Lawson BR, Manenkova Y, Ahamed J, et al. Inhibition of transmethylation down-regulates CD4 T cell activation and curtails development of autoimmunity in a model system. J Immunol. 2007;178:5366–5374.
  • Fu YF, Zhu YN, Ni J, et al. A reversible S-adenosyl-L-homocysteine hydrolase inhibitor ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell activation. J Pharmacol Exp Ther. 2006;319:799–808.
  • Brown PM, Pratt AG, Isaacs JD. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol. 2016;12:731–742.
  • Joseph J, Loscalzo J. Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology. Nutrients. 2013;5:3235–3256.
  • Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev. 2003;8:7–19. Epub 2003/03/04.
  • Oaks Z, Perl A. Metabolic control of the epigenome in systemic lupus erythematosus. Autoimmunity. 2014;47:256–264.
  • Yang ML, Gee AJ, Gee RJ, et al. Lupus autoimmunity altered by cellular methylation metabolism. Autoimmunity. 2013;46:21–31.
  • Krishna SM, Dear A, Craig JM, et al. The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation. Atherosclerosis. 2013;228:295–305.
  • Grillo MA, Colombatto S. S-adenosylmethionine and protein methylation. Amino Acids. 2005;28:357–362. Epub 2005/04/20.
  • Hote PT, Sahoo R, Jani TS, et al. Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression. J Nutr Biochem. 2008;19: 384–391. Epub 2007/09/18.
  • Garcia-Alvarez F, Navarro-Zorraquino M, Larrad L, et al. S-adenosylmethionine immunomodulator treatment in sepsis. Int J Surg Investig. 2000;2: 9–15. Epub 2003/05/31.
  • Ara AI, Xia M, Ramani K, et al. S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. Hepatology (Baltimore, MD). 2008;47: 1655–1666. Epub 2008/04/09.
  • Ding W, Smulan LJ, Hou NS, et al. s-Adenosylmethionine levels govern innate immunity through distinct methylation-dependent pathways. Cell Metab. 2015;22:633–645. Epub 2015/09/01.
  • Gomez-Santos L, Luka Z, Wagner C, et al. Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase. Hepatology (Baltimore, Md). 2012;56: 747–759. Epub 2012/03/07.
  • Bardag-Gorce F, Oliva J, Lin A, et al. SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes. Exp Mol Pathol. 2010;88: 376–379. Epub 2010/03/09.
  • Brooks WH, Le Dantec C, Pers JO, et al. Epigenetics and autoimmunity. J Autoimmun. 2010;34:J207–19.
  • Brooks WH. Autoimmune diseases and polyamines. Clin Rev Allergy Immunol. 2012;42:58–70.
  • Khare P, Jaiswal AK, Tripathi CD, et al. Immunoprotective responses of T helper type 1 stimulatory protein-S-adenosyl-L-homocysteine hydrolase against experimental visceral leishmaniasis. Clin Exp Immunol. 2016;185:165–179.
  • Lawson BR, Eleftheriadis T, Tardif V, et al. Transmethylation in immunity and autoimmunity. Clin Immunol. 2012;143:8–21. Epub 2012/03/01.
  • Jenner RG, Townsend MJ, Jackson I, et al. The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc Natl Acad Sci USA. 2009;106:17876–17881. Epub 2009/10/07.
  • Szabo SJ, Sullivan BM, Peng SL, et al. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2003;21: 713–758. Epub 2002/12/26.
  • Merrill JT, Shen C, Schreibman D, et al. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum. 1997;40: 1308–1315. Epub 1997/07/01.
  • Hasko G, Linden J, Cronstein B, et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008;7:759–770. Epub 2008/09/02.
  • Panther E, Idzko M, Herouy Y, et al. Expression and function of adenosine receptors in human dendritic cells. FASEB J. 2001;15: 1963–1970. Epub 2001/09/05.
  • Schnurr M, Toy T, Shin A, et al. Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood. 2004;103: 1391–1397. Epub 2003/10/11.
  • Desrosiers MD, Cembrola KM, Fakir MJ, et al. Adenosine deamination sustains dendritic cell activation in inflammation. J Immunol. 2007;179: 1884–1892. Epub 2007/07/21.
  • Harish A, Hohana G, Fishman P, et al. A3 adenosine receptor agonist potentiates natural killer cell activity. Int J Oncol. 2003;23: 1245–1249. Epub 2003/09/10.
  • Raskovalova T, Huang X, Sitkovsky M, et al. Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J Immunol. 2005;175: 4383–4391. Epub 2005/09/24.
  • Zhang L, Yang N, Wang S, et al. Adenosine 2A receptor is protective against renal injury in MRL/lpr mice. Lupus. 2011;20:667–677. Epub 2010/12/25.
  • Sipka S. Adenosine inhibits the release of arachidonic acid in activated human peripheral mononuclear cells. A proposed model for physiologic and pathologic regulation in systemic lupus erythematosus. Sci World J. 2011;11: 972–980. Epub 2011/04/26.
  • Botta Gordon-Smith S, Ursu S, Eaton S, et al. Correlation of low CD73 expression on synovial lymphocytes with reduced adenosine generation and higher disease severity in juvenile idiopathic arthritis. Arthritis Rheumat. 2015;67: 545–554. Epub 2014/11/25.
  • Varani K, Padovan M, Vincenzi F, et al. A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release. Arthritis Res Ther. 2011;13: R197. Epub 2011/12/08.
  • Mills JH, Alabanza LM, Mahamed DA, et al. Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis. J Neuroinflammation. 2012;9: 193. Epub 2012/08/14.
  • Ingwersen J, Wingerath B, Graf J, et al. Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation. J Neuroinflammation. 2016;13:48. Epub 2016/02/28.
  • Tsutsui S, Schnermann J, Noorbakhsh F, et al. A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci. 2004;24: 1521–1529. Epub 2004/02/13.
  • Sitaraman SV, Merlin D, Wang L, et al. Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. J Clin Invest. 2001;107: 861–869. Epub 2001/04/04.
  • Kolachala V, Asamoah V, Wang L, et al. TNF-alpha upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cmls. 2005;62: 2647–2657. Epub 2005/12/03.
  • Jijon HB, Walker J, Hoentjen F, et al. Adenosine is a negative regulator of NF-kappaB and MAPK signaling in human intestinal epithelial cells. Cell Immunol. 2005;237:86–95. Epub 2006/01/18.
  • Siegmund B, Rieder F, Albrich S, et al. Adenosine kinase inhibitor GP515 improves experimental colitis in mice. J Pharmacol Exp Ther. 2001;296: 99–105. Epub 2000/12/21.
  • Ineichen BV, Keskitalo S, Farkas M, et al. Genetic variants of homocysteine metabolism and multiple sclerosis: a case-control study. Neurosci Lett. 2014;562:75–78. Epub 2014/01/15.
  • Schroecksnadel K, Frick B, Wirleitner B, et al. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol. 2003;134: 53–56. Epub 2003/09/17.
  • Joshi MB, Baipadithaya G, Balakrishnan A, et al. Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps. Sci Rep. 2016;6: 36362. Epub 2016/11/05.
  • Widner B, Leblhuber F, Frick B, et al. Moderate hyperhomocysteinemia and immune activation in Parkinson’s disease. J Neural Trans. 2002;109: 1445–1452. Epub 2002/12/18.
  • Dawson H, Collins G, Pyle R, et al. The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function. Mech Ageing Dev. 2004;125:107–110. Epub 2004/03/24.
  • Zanin RF, Bergamin LS, Morrone FB, et al. Pathological concentrations of homocysteine increases IL-1beta production in macrophages in a P2X7, NF-kB, and erk-dependent manner. Purinergic Signal. 2015;11: 463–470. Epub 2015/08/13.
  • Zhang D, Fang P, Jiang X, et al. Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice. Circ Res. 2012;111: 37–49. Epub 2012/05/26.
  • Triantafyllou N, Evangelopoulos ME, Kimiskidis VK, et al. Increased plasma homocysteine levels in patients with multiple sclerosis and depression. Ann Gen Psychiatry. 2008;7: 17. Epub 2008/09/11.
  • Moghaddasi M, Mamarabadi M, Mohebi N, et al. Homocysteine, vitamin B12 and folate levels in Iranian patients with multiple sclerosis: a case control study. Clin Neurol Neurosurg. 2013;115: 1802–1805. Epub 2013/06/13.
  • Zhu Y, He ZY, Liu HN. Meta-analysis of the relationship between homocysteine, vitamin B(1)(2), folate, and multiple sclerosis. J Clin Neurosci. 2011;18:933–938. Epub 2011/05/17.
  • Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94: 5923–5928. Epub 1997/05/27.
  • Fujimaki C, Hayashi H, Tsuboi S, et al. Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis. Biomarkers. 2009;14: 49–54. Epub 2009/03/14.
  • Li T, Chen Y, Li J, et al. Serum homocysteine concentration is significantly associated with inflammatory/immune factors. PloS One. 2015;10:e0138099. Epub 2015/09/15.
  • Kayacelebi AA, Willers J, Pham VV, et al. Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease. Amino Acids. 2015;47: 1885–1891. Epub 2015/01/27.
  • Ruhs H, Becker A, Drescher A, et al. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia. PloS One. 2012;7: e46015. Epub 2012/10/11.
  • Corvetta A, Della Bitta R, Luchetti MM, et al. 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J Chromatogr. 1991;566: 481–491. Epub 1991/05/31.
  • Lu Q, Kaplan M, Ray D, et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum. 2002;46: 1282–1291. Epub 2002/07/13.
  • Lu Q, Wu A, Tesmer L, et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol. 2007;179: 6352–6358. Epub 2007/10/20.
  • Kaplan MJ, Lu Q, Wu A, et al. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J Immunol. 2004;172: 3652–3661. Epub 2004/03/09.
  • Javierre BM, Fernandez AF, Richter J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20: 170–179. Epub 2009/12/24.
  • Rodriguez-Cortez VC, Hernando H, de la Rica L, et al. Epigenomic deregulation in the immune system. Epigenomics. 2011;3:697–713. Epub 2011/12/01.
  • Liu Y, Liao J, Zhao M, et al. Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications. Eur J Immunol. 2015;45: 2683–2693. Epub 2015/06/17.
  • Zhang Z, Shi L, Dawany N, et al. H3K4 tri-methylation breadth at transcription start sites impacts the transcriptome of systemic lupus erythematosus. Clin Epigenet. 2016;8:14. Epub 2016/02/04.
  • Brahms H, Raymackers J, Union A, et al. The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J Biol Chem. 2000;275: 17122–17129. Epub 2000/04/05.
  • Chang HH, Hu HH, Lee YJ, et al. Proteomic analyses and identification of arginine methylated proteins differentially recognized by autosera from anti-Sm positive SLE patients. J Biomed Sci. 2013;20: 27. Epub 2013/05/07.
  • Kennedy A, Schmidt EM, Cribbs AP, et al. A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells. Eur J Immunol. 2014;44: 2968–2978. Epub 2014/07/22.
  • Neidhart M, Rethage J, Kuchen S, et al. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum. 2000;43: 2634–2647. Epub 2001/01/06.
  • Stanczyk J, Ospelt C, Karouzakis E, et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 2011;63: 373–381. Epub 2011/02/01.
  • Guo J, Qian L, Li XP, et al. Peptidyl arginine deiminase 4 participates in the pathogenesis of rheumatoid arthritis by influencing histone methylation. Zhonghua Nei Ke Za Zhi. 2013;52: 928–931. Epub 2014/01/21.
  • Bos SD, Page CM, Andreassen BK, et al. Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. PloS One. 2015;10:e0117403. Epub 2015/03/04.
  • Mangano K, Fagone P, Bendtzen K, et al. Hypomethylating agent 5-aza-2ʹ-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models. J Cell Physiol. 2014;229: 1918–1925. Epub 2014/04/05.
  • Kumagai C, Kalman B, Middleton FA, et al. Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol. 2012;246: 51–57. Epub 2012/03/31.
  • Calabrese R, Zampieri M, Mechelli R, et al. Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood. Mult Scler. 2012;18: 299–304. Epub 2011/09/01.
  • Karatzas PS, Mantzaris GJ, Safioleas M, et al. DNA methylation profile of genes involved in inflammation and autoimmunity in inflammatory bowel disease. Medicine. 2014;93: e309. Epub 2014/12/20.
  • Fitzpatrick DR, Wilson CB. Methylation and demethylation in the regulation of genes, cells, and responses in the immune system. Clin Immunol. 2003;109:37–45. Epub 2003/10/31.
  • Suarez-Alvarez B, Rodriguez RM, Fraga MF, et al. DNA methylation: a promising landscape for immune system-related diseases. TIG. 2012;28: 506–514. Epub 2012/07/25.
  • Thielens A, Vivier E, Romagne F. NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol. 2012;24: 239–245. Epub 2012/01/24.
  • Oakes CC, Seifert M, Assenov Y, et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet. 2016;48:253–264.
  • Hata K, Mizuguchi J. Arginine methylation regulates antibody responses through modulating cell division and isotype switching in B cells. Microbiol Immunol. 2013;57: 185–192. Epub 2013/01/03.
  • Tikhanovich I, Kuravi S, Artigues A, et al. Dynamic arginine methylation of tumor necrosis factor (TNF) receptor-associated factor 6 regulates Toll-like receptor signaling. J Biol Chem. 2015;290: 22236–22249. Epub 2015/07/30.
  • Santangelo S, Cousins DJ, Winkelmann NE, et al. DNA methylation changes at human Th2 cytokine genes coincide with DNase I hypersensitive site formation during CD4(+) T cell differentiation. J Immunol. 2002;169: 1893–1903. Epub 2002/08/08.
  • Thomas RM, Gao L, Wells AD. Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. J Immunol. 2005;174: 4639–4646. Epub 2005/04/09.
  • Steinfelder S, Floess S, Engelbert D, et al. Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. Blood. 2011;117: 2839–2846. Epub 2011/01/14.
  • Zajacova M, Kotrbova-Kozak A, Cepek P, et al. Differences in promoter DNA methylation and mRNA expression of individual alleles of the HLA class II DQA1 gene. Immunol Lett. 2015;167:147–154. Epub 2015/08/25.
  • Garaud S, Le Dantec C, Jousse-Joulin S, et al. IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. J Immunol. 2009;182:5623–5632.
  • Karouzakis E, Rengel Y, Jungel A, et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun. 2011;12:643–652. Epub 2011/07/15.
  • Glossop JR, Haworth KE, Emes RD, et al. DNA methylation profiling of synovial fluid FLS in rheumatoid arthritis reveals changes common with tissue-derived FLS. Epigenomics. 2015;7: 539–551. Epub 2015/06/26.
  • Yang G, Wu D, Zeng G, et al. Correlation between miR-126 expression and DNA hypomethylation of CD4+ T cells in rheumatoid arthritis patients. Int J Clin Exp Pathol. 2015;8: 8929–8936. Epub 2015/10/16.
  • Fagone P, Mangano K, Di Marco R, et al. Expression of DNA methylation genes in secondary progressive multiple sclerosis. J Neuroimmunol. 2016;290: 66–69. Epub 2015/12/30.
  • Low D, Mizoguchi A, Mizoguchi E. DNA methylation in inflammatory bowel disease and beyond. World J Gastroenter. 2013;19:5238–5249. Epub 2013/08/29.
  • Lu Q, Renaudineau Y, Cha S, et al. Epigenetics in autoimmune disorders: highlights of the 10th Sjogren’s syndrome symposium. Autoimmun Rev. 2010;9: 627–630. Epub 2010/05/11.
  • Konsta OD, Thabet Y, Le Dantec C, et al. The contribution of epigenetics in Sjogren’s Syndrome. Front Genet. 2014;5: 71. Epub 2014/04/26.
  • 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;1743:205–213.
  • Detich N, Hamm S, Just G, et al. The methyl donor S-adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. J Biol Chem. 2003;278:20812–20820.
  • Dees C, Schlottmann I, Funke R, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis. 2014;73:1232–1239.
  • Schanche JS, Schanche T, Ueland PM, et al. Inactivation and reactivation of intracellular S-adenosylhomocysteinase in the presence of nucleoside analogues in rat hepatocytes. Cancer Res. 1984;44: 4297–4302. Epub 1984/10/01.
  • Della Ragione F, Pegg AE. Effect of analogues of 5ʹ-methylthioadenosine on cellular metabolism. Inactivation of S-adenosylhomocysteine hydrolase by 5ʹ-isobutylthioadenosine. Biochem J. 1983;210: 429–435. Epub 1983/02/15.
  • Gordon RK, Ginalski K, Rudnicki WR, et al. Anti-HIV-1 activity of 3-deaza-adenosine analogs. Eur J Biochem. 2003;270:3507–3517.
  • Flexner CW, Hildreth JE, Kuncl RW, et al. 3-Deaza-adenosine and inhibition of HIV. Lancet. 1992;339:438. Epub 1992/02/15.
  • Wolos JA, Frondorf KA, Esser RE. Immunosuppression mediated by an inhibitor of S-adenosyl-L-homocysteine hydrolase. Prevention and treatment of collagen-induced arthritis. J Immunol. 1993;151:526–534. Epub 1993/07/01.
  • Lambert LE, Frondorf KA, Berling JS, et al. Effects of an S-adenosyl-L-homocysteine hydrolase inhibitor on murine macrophage activation and function. Immunopharmacology. 1995;29: 121–127. Epub 1995/03/01.
  • Saso Y, Conner EM, Teegarden BR, et al. S-adenosyl-L-homocysteine hydrolase inhibitor mediates immunosuppressive effects in vivo: suppression of delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis. J Pharmacol Exp Ther. 2001;296:106–112. Epub 2000/12/21.
  • Garcia GE, Truong LD, Chen JF, et al. Adenosine A(2A) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation. Kidney Int. 2011;80: 378–388. Epub 2011/04/22.
  • Loram LC, Strand KA, Taylor FR, et al. Adenosine 2A receptor agonism: a single intrathecal administration attenuates motor paralysis in experimental autoimmune encephalopathy in rats. Brain Behav Immun. 2015;46:50–54. Epub 2015/02/06.
  • Fishman P, Bar-Yehuda S, Madi L, et al. The PI3K-NF-kappaB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant-induced arthritis. Arthritis Res Ther. 2006;8: R33. Epub 2006/03/02.
  • Butler M, Sanmugalingam D, Burton VJ, et al. Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo. Eur J Immunol. 2012;42: 3358–3368. Epub 2012/10/03.
  • Ham J, Rees DA. The adenosine a2b receptor: its role in inflammation. Endocr Metab Immune Disord Drug Targets. 2008;8:244–254. Epub 2008/12/17.
  • Wei W, Du C, Lv J, et al. Blocking A2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation. J Immunol. 2013;190: 138–146. Epub 2012/12/12.
  • Kominsky DJ, Keely S, MacManus CF, et al. An endogenously anti-inflammatory role for methylation in mucosal inflammation identified through metabolite profiling. J Immunol. 2011;186:6505–6514.
  • Essouma M, Noubiap JJ. Therapeutic potential of folic acid supplementation for cardiovascular disease prevention through homocysteine lowering and blockade in rheumatoid arthritis patients. Biomarker Res. 2015;3:24.
  • Hosea Blewett HJ. Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis. Crit Rev Food Sci Nutr. 2008;48:458–463.
  • Kim J, Lee EY, Koh EM, et al. Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients. Clin Ther. 2009;31: 2860–2872. Epub 2010/01/30.
  • Chan MW, Chang CB, Tung CH, et al. Low-dose 5-aza-2ʹ-deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells. Mol Med. 2014;20:248–256.
  • Cao Q, Wang X, Jia L, et al. Inhibiting DNA methylation by 5-Aza-2′-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology. 2014;155:4925–4938.
  • Veale BJ, Jablonski RY, Frech TM, et al. Orofacial manifestations of systemic sclerosis. Br Dent J. 2016;221:305–310.
  • Zhang YM, Ding Y, Tang W, et al. Synthesis and biological evaluation of immunosuppressive agent DZ2002 and its stereoisomers. Bioorg Med Chem. 2008;16:9212–9216.
  • Wu QL, Fu YF, Zhou WL, et al. Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression. J Pharmacol Exp Ther. 2005;313:705–711.
  • Fu YF, Wang JX, Zhao Y, et al. S-adenosyl-L-homocysteine hydrolase inactivation curtails ovalbumin-induced immune responses. J Pharmacol Exp Ther. 2006;316:1229–1237.
  • Duffy SS, Lees JG, Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;2014:285245.
  • Wu YW, Tang W, Zuo JP. Toll-like receptors: potential targets for lupus treatment. Acta Pharmacol Sin. 2015;36:1395–1407.
  • Wnuk SF. Targeting “hydrolytic” activity of the S-adenosyl-L-homocysteine hydrolase. Mini Rev Med Chem. 2001;1:307–316. Epub 2002/10/09.
  • Moreno B, Fernandez-Diez B, Di Penta A, et al. Preclinical studies of methylthioadenosine for the treatment of multiple sclerosis. Mult Scler. 2010;16:1102–1108.
  • Moreno B, Hevia H, Santamaria M, et al. Methylthioadenosine reverses brain autoimmune disease. Ann Neurol. 2006;60:323–334.
  • Jeong SY, Ahn SG, Lee JH, et al. 3-deazaadenosine, a S-adenosylhomocysteine hydrolase inhibitor, has dual effects on NF-kappaB regulation. Inhibition of NF-kappaB transcriptional activity and promotion of IkappaBalpha degradation. J Biol Chem. 1999;274: 18981–18988. Epub 1999/06/26.
  • Jurgensen CH, Huber BE, Zimmerman TP, et al. 3-deazaadenosine inhibits leukocyte adhesion and ICAM-1 biosynthesis in tumor necrosis factor-stimulated human endothelial cells. J Immunol. 1990;144: 653–661. Epub 1990/01/15.
  • Shea TB, Ashline D, Ortiz D, et al. The S-adenosyl homocysteine hydrolase inhibitor 3-deaza-adenosine prevents oxidative damage and cognitive impairment following folate and vitamin E deprivation in a murine model of age-related, oxidative stress-induced neurodegeneration. Neuromolecular Med. 2004;5: 171–180. Epub 2004/04/13.
  • Bray M, Driscoll J, Huggins JW. Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor. Antiviral Res. 2000;45: 135–147. Epub 2000/05/16.
  • Bitonti AJ, Baumann RJ, Jarvi ET, et al. Antimalarial activity of a 4ʹ,5ʹ-unsaturated 5ʹ-fluoroadenosine mechanism-based inhibitor of S-adenosyl-L-homocysteine hydrolase. Biochem Pharmacol. 1990;40: 601–606. Epub 1990/08/01.
  • Wolos JA, Frondorf KA, Davis GF, et al. Selective inhibition of T cell activation by an inhibitor of S-adenosyl-L-homocysteine hydrolase. J Immunol. 1993;150:3264–3273. Epub 1993/04/15.
  • Ault-Riche DB, Lee Y, Yuan CS, et al. Effects of 4ʹ-modified analogs of aristeromycin on the metabolism of S-adenosyl-L-homocysteine in murine L929 cells. Mol Pharmacol. 1993;43: 989–997. Epub 1993/06/01.
  • Zhang M, Li XL, Li H, et al. Activation of the adenosine A2A receptor exacerbates experimental autoimmune neuritis in Lewis rats in association with enhanced humoral immunity. J Neuroimmunol. 2016;293: 129–136. Epub 2016/04/07.
  • Bar-Yehuda S, Silverman MH, Kerns WD, et al. The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs. 2007;16:1601–1613. Epub 2007/10/10.
  • Rath-Wolfson L, Bar-Yehuda S, Madi L, et al. IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Clin Exp Rheumatol. 2006;24: 400–406. Epub 2006/09/08.
  • Mustafa SJ, Nadeem A, Fan M, et al. Effect of a specific and selective A(2B) adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma. J Pharmacol Exp Ther. 2007;320: 1246–1251. Epub 2006/12/13.
  • Zhao M, Zhou Y, Zhu B, et al. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis. 2016;75:1998–2006.
  • Suzuki S, Kodera Y, Saito T, et al. Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress. Sci Rep. 2016;6:38299.
  • Saad MN, Mabrouk MS, Eldeib AM, et al. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: a systematic review and meta-analysis. J Advan Res. 2016;7:1–16.
  • Abbenhardt C, Miller JW, Song X, et al. Biomarkers of one-carbon metabolism are associated with biomarkers of inflammation in women. J Nutr. 2014;144:714–721.

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