Selective Activation of Adenosine A2A Receptors on Immune Cells by a CD73-Dependent Prodrug Suppresses Joint Inflammation in Experimental Rheumatoid Arthritis

被引：109

作者：

Floegel, Ulrich ^{[1
]}

Burghoff, Sandra ^{[1
]}

van Lent, Peter L. E. M. ^{[2
]}

Temme, Sebastian ^{[1
]}

Galbarz, Lisa ^{[1
]}

Ding, Zhaoping ^{[1
]}

El-Tayeb, Ali ^{[3
]}

Huels, Sandra ^{[1
]}

Boenner, Florian ^{[1
]}

Borg, Nadine ^{[1
]}

Jacoby, Christoph ^{[1
]}

Mueller, Christa E. ^{[3
]}

van den Berg, Wim B. ^{[2
]}

Schrader, Juergen ^{[1
]}

机构：

[1] Univ Dusseldorf, Dept Mol Cardiol, D-40225 Dusseldorf, Germany

[2] Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, NL-6525 ED Nijmegen, Netherlands

[3] Univ Bonn, PharmaCtr Bonn, Inst Pharmaceut, D-53121 Bonn, Germany

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2012年 / 4卷 / 146期

关键词：

NECROSIS-FACTOR-ALPHA; REGULATORY T-CELLS; IN-VIVO; PULMONARY INFLAMMATION; CARTILAGE DESTRUCTION; ADENINE-NUCLEOTIDES; DEFICIENT MICE; EXPRESSION; DISEASE; CD73/ECTO-5'-NUCLEOTIDASE;

D O I：

10.1126/scitranslmed.3003717

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Adenosine A(2A) receptor (A(2A)R) agonists are both highly effective anti-inflammatory agents and potent vasodilators. To separate these two activities, we have synthesized phosphorylated A(2A)R agonists (prodrugs) that require the presence of ecto-5'-nucleotidase (CD73) to become activated. In the model of collagen- induced arthritis, 2-(cyclohexylethylthio)adenosine 5'-monophosphate (chet-AMP), but not 2-(cyclohexylethylthio)adenosine (chet-adenosine), potently reduced inflammation as assessed by fluorine-19 (F-19) magnetic resonance imaging and by histology. The prodrug effect was blunted by inhibition of CD73 and A(2A)R. The selectivity of drug action is due to profound up-regulation of CD73 and adenosine A(2A)R expression in neutrophils and inflammatory monocytes as found in recovered cells from the synovial fluid of arthritic mice. Plasma chet-adenosine was in the subnanomolar range when chet-AMP was applied, whereas concentrations required for vasodilation were about 100 times higher. Thus, chet-AMP is a potent immunosuppressant with negligible vasodilatory activity. These data suggest that phosphorylated A(2A)R agonists may serve as a promising new group of drugs for targeted immunotherapy of inflammation.

引用

页数：8

共 48 条

[21] Tumor Necrosis Factor-Interleukin-17 Interplay Induces S100A8, Interleukin-1β, and Matrix Metalloproteinases, and Drives Irreversible Cartilage Destruction In Murine Arthritis Rationale for Combination Treatment During Arthritis [J].

Koenders, Marije I. ;

Marijnissen, Renoud J. ;

Devesa, Isabel ;

Lubberts, Erik ;

Joosten, Leo A. B. ;

Roth, Johannes ;

van Lent, Peter L. E. M. ;

van de Loo, Fons A. ;

van den Berg, Wim B. .

ARTHRITIS AND RHEUMATISM, 2011, 63 (08) :2329-2339

[22] Targeted disruption of cd73/ecto-5′-nucleotidase alters thromboregulation and augments vascular inflammatory response [J].

Koszalka, P ;

Özüyaman, B ;

Huo, YQ ;

Zernecke, A ;

Flögel, U ;

Braun, N ;

Buchheiser, A ;

Decking, UKM ;

Smith, ML ;

Sévigny, J ;

Gear, A ;

Weber, AA ;

Molojavyi, A ;

Ding, ZP ;

Weber, C ;

Ley, K ;

Zimmermann, H ;

Gödecke, A ;

Schrader, J .

CIRCULATION RESEARCH, 2004, 95 (08) :814-821

[23] A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells [J].

Lappas, CM ;

Rieger, JM ;

Linden, J .

JOURNAL OF IMMUNOLOGY, 2005, 174 (02) :1073-1080

[24]

Linden J, 2011, ADV PHARMACOL, V61, P95, DOI 10.1016/B978-0-12-385526-8.00004-7

[25] Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs [J].

Lukashev, DE ;

Smith, PT ;

Caldwell, CC ;

Ohta, A ;

Apasov, SG ;

Sitkovsky, MV .

BIOCHEMICAL PHARMACOLOGY, 2003, 65 (12) :2081-2090

[26] The antiinflammatory mechanism ot methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5′-nucleotidase -: Findings in a study of ecto-5′-nucleotidase gene-deficient mice [J].

Montesinos, M. Carmen ;

Takedachi, Masahide ;

Thompson, Linda F. ;

Wilder, Tuere F. ;

Fernandez, Patricia ;

Cronstein, Bruce N. .

ARTHRITIS AND RHEUMATISM, 2007, 56 (05) :1440-1445

[27] Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides [J].

Morabito, L ;

Montesinos, MC ;

Schreibman, DM ;

Balter, L ;

Thompson, LF ;

Resta, R ;

Carlin, G ;

Huie, MA ;

Cronstein, BN .

JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (02) :295-300

[28] Recent developments in adenosine receptor ligands and their potential as novel drugs [J].

Mueller, Christa E. ;

Jacobson, Kenneth A. .

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2011, 1808 (05) :1290-1308

[29] Clinical Utility of Regadenoson for Assessing Fractional Flow Reserve [J].

Nair, Pradeep K. ;

Marroquin, Oscar C. ;

Mulukutla, Suresh R. ;

Khandhar, Sameer ;

Gulati, Vijay ;

Schindler, John T. ;

Lee, Joon S. .

JACC-CARDIOVASCULAR INTERVENTIONS, 2011, 4 (10) :1085-1092

[30] Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice [J].

Nakae, S ;

Nambu, A ;

Sudo, K ;

Iwakura, Y .

JOURNAL OF IMMUNOLOGY, 2003, 171 (11) :6173-6177

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