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Journal of Inflammation
Published in: Journal of Inflammation 1/2015

Open Access 01-12-2015 | Research

Anti-inflammatory effects of adenosine N1-oxide

Authors: Keizo Kohno, Emiko Ohashi, Osamu Sano, Hajime Kusano, Toshio Kunikata, Norie Arai, Toshiharu Hanaya, Toshio Kawata, Tomoyuki Nishimoto, Shigeharu Fukuda

Published in: Journal of Inflammation | Issue 1/2015

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Abstract

Background

Adenosine is a potent endogenous anti-inflammatory and immunoregulatory molecule. Despite its promise, adenosine’s extremely short half-life in blood limits its clinical application. Here, we examined adenosine N1-oxide (ANO), which is found in royal jelly. ANO is an oxidized product of adenosine at the N1 position of the adenine base moiety. We found that it is refractory to adenosine deaminase-mediated conversion to inosine. We further examined the anti-inflammatory activities of ANO in vitro and in vivo.

Methods

The effect of ANO on pro-inflammatory cytokine secretion was examined in mouse peritoneal macrophages and the human monocytic cell line THP-1, and compared with that of adenosine, synthetic adenosine receptor (AR)-selective agonists and dipotassium glycyrrhizate (GK2). The anti-inflammatory activity of ANO in vivo was examined in an LPS-induced endotoxin shock model in mice.

Results

ANO inhibited secretion of inflammatory mediators at much lower concentrations than adenosine and GK2 when used with peritoneal macrophages and THP-1 cells that were stimulated by LPS plus IFN-γ. The potent anti-inflammatory activity of ANO could not be solely accounted for by its refractoriness to adenosine deaminase. ANO was superior to the synthetic A1 AR-selective agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), A2A AR-selective agonist, 2-[p-(2-carboxyethyl)phenethylamino]-5’-N-ethylcarboxamideadenosine hydrochloride (CGS21680), and A3 AR-selective agonist, N6-(3-iodobenzyl)adenosine-5’-N-methyluronamide (IB-MECA), in suppressing the secretion of a broad spectrum of pro-inflammatory cytokines by peritoneal macrophages. The capacities of ANO to inhibit pro-inflammatory cytokine production by THP-1 cells were comparable with those of CCPA and IB-MECA. Reflecting its potent anti-inflammatory effects in vitro, intravenous administration of ANO significantly reduced lethality of LPS-induced endotoxin shock. A significant increase in survival rate was also observed by oral administration of ANO. Mechanistic analysis suggested that the up-regulation of the anti-inflammatory transcription factor c-Fos was, at least in part, involved in the ANO-induced suppression of pro-inflammatory cytokine secretion.

Conclusions

Our data suggest that ANO, a naturally occurring molecule that is structurally close to adenosine but is functionally more potent, presents potential strategies for the treatment of inflammatory disorders.
Literature
1.
Ashley NT, Weil ZM, Nelson RJ. Inflammation: mechanisms, costs, and natural variation. Ann Rev Ecol Evol Syst. 2012;43:385–406.CrossRef
2.
Jin J, Chang Y, Wei W. Clinical application and evaluation of anti-TNF-α agents for the treatment of rheumatoid arthritis. Acta Pharmacol Sin. 2010;31(9):1133–40.PubMedCentralPubMedCrossRef
3.
Magro F, Portela F. Management of inflammatory bowel disease with infliximab and other anti-tumor necrosis factor α therapies. Bio Drugs. 2010;24 Suppl 1:3–14.
4.
5.
Laws PM, Young HS. Current and emerging systemic treatment strategies for psoriasis. Drugs. 2012;72(14):1867–80.PubMedCrossRef
6.
Hasko G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008;7(9):759–70.PubMedCentralPubMedCrossRef
7.
Hasko G, Cronstein BN. Adenosine: an endogenous regulator of innate immunity. Trends Immunol. 2004;25(1):33–9.PubMedCrossRef
8.
9.
Milne GR, Palmer TM. Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. Scientific World J. 2011;11:320–39.CrossRef
10.
11.
Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol. 1983;93(1–2):21–6.PubMedCrossRef
12.
Clementina M, Giuseppe S. A2A receptor ligands: past, present and future trends. Curr Top Med Chem. 2010;10(9):902–22.PubMedCrossRef
13.
14.
Nakav S, Chaimovitz C, Sufaro Y, Lewis EC, Shaked G, Czeiger D, Zlotnik M, Douvdevani A. Anti-inflammatory preconditioning by agonists of adenosine A1 receptor. PLos One. 2008;3(5):e2107.PubMedCentralPubMedCrossRef
15.
Ehrentraut H, Westrich JA, Eltzschig H, Clambey ET. Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation. PLos One. 2012;7(2):e32416.PubMedCentralPubMedCrossRef
16.
Montesions MC, Desai A, Delano D, Chen JF, Fink JS, Jacobson MA, Cronstein BN. Adenosine A2a or A3 receptors are required for inhibition of inflammation by methotrexate. Arthritis Rheum. 2002;48(1):240–7.CrossRef
17.
Kohno K, Okamoto I, Sano O, Arai N, Iwaki K, Ikeda M, Kurimoto M. Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages. Biosci Biotechnol Biochem. 2004;68(1):138–45.PubMedCrossRef
18.
Hattori N, Nomoto H, Mishima S, Inagaki S, Goto M, Sako M, Furukawa S. Identification of AMP N1-Oxide in royal jelly as a component neurotrophic toward cultured rat pheochromocytpoma PC12 cells. Biosci Biotechnol Biochem. 2006;70(4):897–906.PubMedCrossRef
19.
Stevens MA, Magrath DI, Smith HW, Brown GB. Purine N-Oxides. I Mono-oxides of aminopurines J Am Chem Soc. 1958;80(11):2755–8.CrossRef
20.
Tateyama S, Horisawa K, Takashima H, Miyamoto-Sato E, Doi N, Yanagawa H. Affinity selection of DNA-binding protein complexes using mRNA display. Nucleic Acids Res. 2006;34(3):e27.PubMedCentralPubMedCrossRef
21.
Southworth T, Metryka A, Lea S, Farrow S, Plumb J, Singh D. IFN-γ synergistically enhances LPS signaling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation. Br J Pharmacol. 2012;166:2070–83.PubMedCentralPubMedCrossRef
22.
Car BD, Eng VM, Schnyder B, Ozmen L, Huang S, Gallay P, Heumann D, Aguet M, Ryffel B. Interferon γ receptor deficient mice are resistant to endotoxic shock. J Exp Med. 1994;179(5):1437–44.PubMedCrossRef
23.
Kato T, Horie N, Hashimoto K, Satoh K, Shimoyama T, Kaneko T, Kusama K, Sakagami H. Bimodal effect of glycyrrhizin on macrophage nitric oxide and prostaglandin E2 production. In vivo. 2008;22:583–6.PubMed
24.
Ohira H, Fujioka Y, Katagiri C, Yano M, Mamoto R, Aoyama M, Usami M, Ikeda M. Butyrate enhancement of interleukin-1β production via activation of oxidative stress pathways in lipopolysaccharide-stimulated THP-1 cells. J Clin Biochem Nutr. 2012;50(1):59–66.PubMedCentralPubMedCrossRef
25.
Dinarello CA. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest. 1997;112(6 Suppl):321S–9S.PubMedCrossRef
26.
Wall EA, Zavzavadjian JR, Cahng MS, Randhawa B, Zhu X, Liu RJ, Driver A, Bao XR, Sternweis P, Simon MI. Suppression of LPS-induced TNF-α production in macrophages by cAMP is mediated by PKA-AKAP95-p105. Sci Signal. 2009;2(75):ra28.PubMedCentralPubMedCrossRef
27.
Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A. Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the phosphorylated c-Fos protein. Immunity. 2009;30:372–83.PubMedCrossRef
28.
Taniguchi Y, Kohno K, Inoue S, Koya-Miyata S, Okamoto I, Arai N, Iwaki K, Ikeda M, Kurimoto M. Oral administration of royal jelly inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice. Int Immunopharmacol. 2003;3(9):1313–24.PubMedCrossRef
29.
Xue XF, Zhou JH, Wu LM, Fu LH, Zhao J. HPLC determination of adenosine in royal jelly. Food Chemistry. 2009;115:715–9.CrossRef
30.
Sano O, Kunikata T, Kohno K, Iwaki K, Ikeda M, Kurimoto M. Characterization of royal jelly proteins in both Africanized and European honeybees (Apis mellifera) by two-dimensional gel electrophoresis. J Agric Food Chem. 2004;52(1):15–20.PubMedCrossRef
31.
32.
Ramakers BP, Riksen NP, Rongen GA, van der Hoeven JG, Smits P, Pickkers P. The effect of adenosine receptor agonists on cytokine release by human mononuclear cells depends on the specific Toll-like receptor subtype used for stimulation. Cytokine. 2006;35(1–2):95–9.PubMedCrossRef
33.
Fredholm BB, Cunha RA, Svenningsson P. Pharmacology of adenosine A2a receptors and therapeutic applications. Curr Top Med Chem. 2002;3:1349–64.
34.
Kull B, Arslan G, Nilsson C, Owman C, Lorenzen A, Schwabe U, Fredholm BB. Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors. Biochem Pharmacol. 1999;57:65–75.PubMedCrossRef
35.
Yildiz G, Demiryurek AT, Gumusel B, Lippton H. Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: role of adenosine receptors. Eur J Pharmacol. 2007;556(1–3):144–50.PubMedCrossRef
36.
Ngamsri KC, Wagner R, Vollmer I, Stark S, Reutershan J. Adenosine receptor A1 regulates polymorphonuclear cell trafficking and microvascular permeability in lipopolysaccharide-induced lung injury. J Immunol. 2010;185(7):4374–84.PubMedCrossRef
37.
Schingnitz U, Hartmann K, MacManus CF, Eckle T, Zug S, Colgan SP, Eltzschig HK. Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol. 2010;184(9):5271–9.PubMedCentralPubMedCrossRef
38.
Martin L, Pingle SC, Hallam DM, Rybak LP, Ramkumar V. Activation of the adenosine A3 receptor in RAW264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-α release by reducing calcium-dependent activation of nuclear factor-κB and extracellular signal-regulated kinase 1/2. J Pharmacol Exp Ther. 2006;316(1):71–8.PubMedCrossRef
39.
Ham J, Rees DA. The adenosine A2b receptor: Its role in inflammation. Endocr Metab Immune Disord Drug Targets. 2008;8(4):244–54.PubMedCrossRef
40.
Gessi S, Merighi S, Varani K, Leung E, Lennan SM, Borea PA. The A3 adenosine receptor: An enigmatic player in cell biology. Pharmacol Ther. 2008;117(1):123–40.PubMedCrossRef
41.
Parmely M, Zhou WW, Edwards III CK, Borcherding DR, Silverstein R, Morrison DC. Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-α production and protect mice against endotoxin challenge. J Immunol. 1993;151(1):389–96.PubMed
42.
Howard M, Muchamuel T, Andrade S, Menon S. Interleukin 10 protects mice from lethal endotoxemia. J Exp Med. 1993;177(4):1205–8.PubMedCrossRef
43.
Hasko G, Nemeth ZH, Vizi ES, Salzman AL, Szabo C. An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-γ production and prevents lethality in endotoxemic mice. Eur J Pharmacol. 1998;358:261–8.PubMedCrossRef
44.
Kreckler LM, Gizewski E, Wan TC, Auchampach JA. Adenosine suppresses lipopolysaccharide-induced tumor necrosis factor-α production by murine macrophages through a protein kinase A- and exchange protein activated by cAMP-independent signaling pathway. J Pharmacol Exp Ther. 2009;331(3):1051–61.PubMedCentralPubMedCrossRef
45.
Ray N, Kuwahara M, Takada Y, Maruyama K, Kawaguchi T, Tsuboe H, Ishikawa H, Matsuo K. c-Fos suppresses systemic inflammatory response to endotoxin. Int Immunol. 2006;18(5):671–7.PubMedCrossRef
Metadata
Title
Anti-inflammatory effects of adenosine N1-oxide
Authors
Keizo Kohno
Emiko Ohashi
Osamu Sano
Hajime Kusano
Toshio Kunikata
Norie Arai
Toshiharu Hanaya
Toshio Kawata
Tomoyuki Nishimoto
Shigeharu Fukuda
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Inflammation / Issue 1/2015
Electronic ISSN: 1476-9255
DOI
https://doi.org/10.1186/s12950-014-0045-0

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