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Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells

  • Research Article
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Journal of Cell Communication and Signaling Aims and scope

Abstract

Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A2A (A2AAR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A2B and A3) and that A2AAR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A2AAR-silencing amplified NR4A induction by NECA. Interestingly, a similar A2AAR modulatory effect was observed on ERK1/2 phosphorylation because A2AAR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A2AAR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A2AAR activation, not only in the context of adenosine but of other mast cell activating stimuli as well.

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Abbreviations

AR:

Adenosine receptor

HMC-1:

Human mast cell line 1

NBRE-LUC:

Nerve-growth factor I-B responsive element-luciferase reporter gene

NR4A1:

Nuclear orphan receptor 4 A1

NR4A2:

Nuclear orphan receptor 4 A2

NR4A3:

Nuclear orphan receptor 4 A3

PKC:

Protein kinase C

RT-PCR:

Reverse transcriptase polymerase chain reaction

References

  • Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, Weitz J, Koch M, Halverson AL, Bentrem DJ, Khazaie K (2010) In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci U S A 107:6430–6435

    Article  CAS  PubMed  Google Scholar 

  • Brightling CE, Bradding P, Pavord ID, Wardlaw AJ (2003) New insights into the role of the mast cell in asthma. Clin Exp Allergy 33:550–556

    Article  CAS  PubMed  Google Scholar 

  • Chang EY, Szallasi Z, Acs P, Raizada V, Wolfe PC, Fewtrell C, Blumberg PM, Rivera J (1997) Functional effects of overexpression of protein kinase C-alpha, -beta, -delta, -epsilon, and -eta in the mast cell line RBL-2H3. J Immunol 159:2624–2632

    CAS  PubMed  Google Scholar 

  • Cho SH, You HJ, Woo CH, Yoo YJ, Kim JH (2004) Rac and protein kinase C-delta regulate ERKs and cytosolic phospholipase A2 in FcepsilonRI signaling to cysteinyl leukotriene synthesis in mast cells. J Immunol 173:624–631

    CAS  PubMed  Google Scholar 

  • Church MK, Levi-Schaffer F (1997) The human mast cell. J Allergy Clin Immunol 99:155–160

    Article  CAS  PubMed  Google Scholar 

  • Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW (2004) Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting. J Biol Chem 279:53338–53345

    Article  CAS  PubMed  Google Scholar 

  • Driver AG, Kukoly CA, Ali S, Mustafa SJ (1993) Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 148:91–97

    CAS  PubMed  Google Scholar 

  • Fahrner TJ, Carroll SL, Milbrandt J (1990) The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally. Mol Cell Biol 10:6454–6459

    CAS  PubMed  Google Scholar 

  • Feoktistov I, Biaggioni I (1998) Pharmacological characterization of adenosine A2B receptors: studies in human mast cells co-expressing A2A and A2B adenosine receptor subtypes. Biochem Pharmacol 55:627–633

    Article  CAS  PubMed  Google Scholar 

  • Feoktistov I, Goldstein AE, Biaggioni I (1999) Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. Mol Pharmacol 55:726–734

    CAS  PubMed  Google Scholar 

  • Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I (2003) Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res 92:485–492

    Article  CAS  PubMed  Google Scholar 

  • Fozard JR (2003) The case for a role for adenosine in asthma: almost convincing? Curr Opin Pharmacol 3:264–269

    Article  CAS  PubMed  Google Scholar 

  • Groot Kormelink T, Abudukelimu A, Redegeld FA (2009) Mast cells as target in cancer therapy. Curr Pharm Des 15:1868–1878

    Article  CAS  PubMed  Google Scholar 

  • Harant H, Lindley IJ (2004) Negative cross-talk between the human orphan nuclear receptor Nur77/NAK-1/TR3 and nuclear factor-kappaB. Nucleic Acids Res 32:5280–5290

    Article  CAS  PubMed  Google Scholar 

  • Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Molnar Vilagos G, Herjavecz I, Horvath I (2002) Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma. Eur Respir J 20:1393–1398

    Article  CAS  PubMed  Google Scholar 

  • Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264

    Article  CAS  PubMed  Google Scholar 

  • Lammi J, Rajalin AM, Huppunen J, Aarnisalo P (2007) Cross-talk between the NR3B and NR4A families of orphan nuclear receptors. Biochem Biophys Res Commun 359:391–397

    Article  CAS  PubMed  Google Scholar 

  • Mack M, Rosenkranz AR (2009) Basophils and mast cells in renal injury. Kidney Int 76:1142–1147

    Article  PubMed  Google Scholar 

  • Manna PR, Dyson MT, Eubank DW, Clark BJ, Lalli E, Sassone-Corsi P, Zeleznik AJ, Stocco DM (2002) Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Mol Endocrinol 16:184–199

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Gonzalez J, Badimon L (2005) The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells. Cardiovasc Res 65:609–618

    Article  CAS  PubMed  Google Scholar 

  • McEvoy AN, Murphy EA, Ponnio T, Conneely OM, Bresnihan B, FitzGerald O, Murphy EP (2002) Activation of nuclear orphan receptor NURR1 transcription by NF-kappa B and cyclic adenosine 5′-monophosphate response element-binding protein in rheumatoid arthritis synovial tissue. J Immunol 168:2979–2987

    PubMed  Google Scholar 

  • Murphy EP, McEvoy A, Conneely OM, Bresnihan B, FitzGerald O (2001) Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Arthritis Rheum 44:782–793

    Article  CAS  PubMed  Google Scholar 

  • Nilsson G, Blom T, Kusche-Gullberg M, Kjellen L, Butterfield JH, Sundstrom C, Nilsson K, Hellman L (1994) Phenotypic characterization of the human mast-cell line HMC-1. Scand J Immunol 39:489–498

    Article  CAS  PubMed  Google Scholar 

  • Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920

    Article  CAS  PubMed  Google Scholar 

  • Palmer TM, Trevethick MA (2008) Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction. Br J Pharmacol 153(Suppl 1):S27–S34

    CAS  PubMed  Google Scholar 

  • Pei L, Castrillo A, Chen M, Hoffmann A, Tontonoz P (2005) Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J Biol Chem 280:29256–29262

    Article  CAS  PubMed  Google Scholar 

  • Pei L, Castrillo A, Tontonoz P (2006a) Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77. Mol Endocrinol 20:786–794

    Article  CAS  PubMed  Google Scholar 

  • Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P (2006b) NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat Med 12:1048–1055

    Article  CAS  PubMed  Google Scholar 

  • Ralph JA, McEvoy AN, Kane D, Bresnihan B, FitzGerald O, Murphy EP (2005) Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J Immunol 175:555–565

    CAS  PubMed  Google Scholar 

  • Rivera J, Gilfillan AM (2006) Molecular regulation of mast cell activation. J Allergy Clin Immunol 117:1214–1225, quiz 1226

    Article  CAS  PubMed  Google Scholar 

  • Ryzhov S, Goldstein AE, Matafonov A, Zeng D, Biaggioni I, Feoktistov I (2004) Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J Immunol 172:7726–7733

    CAS  PubMed  Google Scholar 

  • Ryzhov S, Goldstein AE, Biaggioni I, Feoktistov I (2006) Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. Mol Pharmacol 70:727–735

    Article  CAS  PubMed  Google Scholar 

  • Spicuzza L, Di Maria G, Polosa R (2006) Adenosine in the airways: implications and applications. Eur J Pharmacol 533:77–88

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Takei M, Nakahata T, Fukamachi H (1998) Inhibitory effect of adenosine on degranulation of human cultured mast cells upon cross-linking of Fc epsilon RI. Biochem Biophys Res Commun 242:697–702

    Article  CAS  PubMed  Google Scholar 

  • Wallen-Mackenzie A, Mata de Urquiza A, Petersson S, Rodriguez FJ, Friling S, Wagner J, Ordentlich P, Lengqvist J, Heyman RA, Arenas E, Perlmann T (2003) Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes Dev 17:3036–3047

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423:555–560

    Article  CAS  PubMed  Google Scholar 

  • Winoto A, Littman DR (2002) Nuclear hormone receptors in T lymphocytes. Cell 109(Suppl):S57–S66

    Article  CAS  PubMed  Google Scholar 

  • Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250

    Article  CAS  PubMed  Google Scholar 

  • Zhou QY, Li C, Olah ME, Johnson RA, Stiles GL, Civelli O (1992) Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci U S A 89:7432–7436

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Felix R. Althaus for his support, and the Functional Genomics Center Zurich (University of Zurich-Irchel) for the assistance with RNA profiling studies. This work has been financed by the Foundation for Scientific Research of the University of Zurich (Stiftung für wissenschaftliche Forschung).

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland

    Li Zhang, Catherine Paine & Ramiro Dip

  2. Institute of Pharmacology and Toxicology, Winterthurerstrasse 260, 8057, Zurich, Switzerland

    Ramiro Dip

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  1. Li Zhang
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  2. Catherine Paine
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  3. Ramiro Dip
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Correspondence to Ramiro Dip.

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Concise summary

Non-selective AR engagement triggers robust induction NR4A orphan receptors in mast cells. Induction of these early responsive genes can be blocked by selective activation of the anti-inflammatory A2AAR not only in the context of adenosine but also of PMA signaling, suggesting a general mechanism of mast cell regulation.

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Zhang, L., Paine, C. & Dip, R. Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells. J. Cell Commun. Signal. 4, 173–183 (2010). https://doi.org/10.1007/s12079-010-0104-0

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  • DOI: https://doi.org/10.1007/s12079-010-0104-0

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