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Expression of P2 receptors at sites of chronic inflammation


Extracellular nucleotides have been identified as important signaling molecules. These nucleotides act on the P2 family of receptors that respond by either forming an ion-channel or by activation of a signal transduction cascade, both of which enable a cellular response. Although a role for P2 receptors in inflammation has been implied, the local expression pattern and kinetics of these receptors at sites of inflammation are not known. Therefore, we have studied the expression of the P2 receptors expressed by inflammatory cells or by cells in the vasculature, with special attention to P2X1R, P2X7R, P2Y1R, and P2Y2R. As a suitable model for studying inflammatory reactions, we have employed the foreign body reaction (FBR), a sterile inflammatory reaction induced by implanting degradable cross-linked dermal sheep collagen disks subcutaneously in the rat. We show that, in the vasculature, the expression of P2X7R, P2Y1R, and P2Y2R increase until day 2. The expression of P2X7R and P2Y1R on macrophages and giant cells increased during the course of the inflammatory reaction which was studied for 21 days. The expression of the P2Y2R on macrophages and giant cells inside the foreign body increases with time, whereas the expression on macrophages in the surrounding tissue is maximal at day 5. The expression of P2X1R remains at a constant low level. The upregulation of P2X7R, P2Y1R, and P2Y2R over time suggests a regulatory function for these receptors in inflammation.

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  1. Albertini M von, Palmetshofer A, Kaczmarek E, Koziak K, Stroka D, Grey ST, Stuhlmeier KM, Robson SC (1998) Extracellular ATP and ADP activate transcription factor NF-kappa B and induce endothelial cell apoptosis. Biochem Biophys Res Commun 248:822–829

  2. Amerongen MJ van, Molema G, Plantinga J, Moorlag H, Luyn MJ van (2002) Neovascularization and vascular markers in a foreign body reaction to subcutaneously implanted degradable biomaterial in mice. Angiogenesis 5:173–180

  3. Baricordi OR, Melchiorri L, Adinolfi E, Falzoni S, Chiozzi P, Buell G, Di Virgilio F (1999) Increased proliferation rate of lymphoid cells transfected with the P2X(7) ATP receptor. J Biol Chem 274:33206–33208

  4. Buvinic S, Briones R, Huidobro-Toro JP (2002) P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br J Pharmacol 136:847–856

  5. Chiozzi P, Sanz JM, Ferrari D, Falzoni S, Aleotti A, Buell GN, Collo G, Di Virgilio F (1997) Spontaneous cell fusion in macrophage cultures expressing high levels of the P2Z/P2X7 receptor. J Cell Biol 138:697–706

  6. Communi D, Janssens R, Suarez-Huerta N, Robaye B, Boeynaems JM (2000) Advances in signalling by extracellular nucleotides. The role and transduction mechanisms of P2Y receptors. Cell Signal 12:351–360

  7. Coutinho-Silva R, Parsons M, Robson T, Lincoln J, Burnstock G (2003) P2X and P2Y purinoceptor expression in pancreas from streptozotocin-diabetic rats. Mol Cell Endocrinol 204:141–154

  8. Dijkstra CD, Dopp EA, Joling P, Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54:589–599

  9. Di Virgilio F, Chiozzi P, Ferrari D, Falzoni S, Sanz JM, Morelli A, Torboli M, Bolognesi G, Baricordi OR (2001) Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97:587–600

  10. Fabre JE, Nguyen M, Latour A, Keifer JA, Audoly LP, Coffman TM, Koller BH (1999) Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice. Nat Med 5:1199–1202

  11. Falzoni S, Chiozzi P, Ferrari D, Buell G, Di Virgilio F (2000) P2X(7) receptor and polykarion formation. Mol Biol Cell 11:3169–3176

  12. Ferrari D, La Sala A, Chiozzi P, Morelli A, Falzoni S, Girolomoni G, Idzko M, Dichmann S, Norgauer J, Di Virgilio F (2000) The P2 purinergic receptors of human dendritic cells: identification and coupling to cytokine release. FASEB J 14:2466–2476

  13. Gitterman DP, Evans RJ (2000) Properties of P2X and P2Y receptors are dependent on artery diameter in the rat mesenteric bed. Br J Pharmacol 131:1561–1568

  14. Harada H, Chan CM, Loesch A, Unwin R, Burnstock G (2000) Induction of proliferation and apoptotic cell death via P2Y and P2X receptors, respectively, in rat glomerular mesangial cells. Kidney Int 57:949–958

  15. Hogquist KA, Nett MA, Unanue ER, Chaplin DD (1991) Interleukin 1 is processed and released during apoptosis. Proc Natl Acad Sci USA 88:8485–8489

  16. Jorgensen NR, Henriksen Z, Sorensen OH, Eriksen EF, Civitelli R, Steinberg TH (2002) Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors. J Biol Chem 277:7574–7580

  17. Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Seguela P, Voigt M, Humphrey PP (2001) International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 53:107–118

  18. Luyn MJ van, Wachem PB van, Damink LO, Dijkstra PJ, Feijen J, Nieuwenhuis P (1992) Relations between in vitro cytotoxicity and crosslinked dermal sheep collagens. J Biomed Mater Res 26:1091–1110

  19. Marrelli SP (2001) Mechanisms of endothelial P2Y(1)- and P2Y(2)-mediated vasodilatation involve differential [Ca2+]i responses. Am J Physiol Heart Circ Physiol 281:H1759–H1766

  20. Marriott I, Inscho EW, Bost KL (1999) Extracellular uridine nucleotides initiate cytokine production by murine dendritic cells. Cell Immunol 195:147–156

  21. McCloskey MA, Fan Y, Luther S (1999) Chemotaxis of rat mast cells toward adenine nucleotides. J Immunol 163:970–977

  22. Molloy A, Laochumroonvorapong P, Kaplan G (1994) Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus Calmette–Guerin. J Exp Med 180:1499–1509

  23. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

  24. Olde Damink LH, Dijkstra PJ, Luyn MJ van, Wachem PB van, Nieuwenhuis P, Feijen J (1996) Cross-linking of dermal sheep collagen using a water-soluble carbodiimide. Biomaterials 17:765–773

  25. Oshimi Y, Miyazaki S, Oda S (1999) ATP-induced Ca2+ response mediated by P2U and P2Y purinoceptors in human macrophages: signalling from dying cells to macrophages. Immunology 98:220–227

  26. Parker AL, Likar LL, Dawicki DD, Rounds S (1996) Mechanism of ATP-induced leukocyte adherence to cultured pulmonary artery endothelial cells. Am J Physiol 270:L695–L703

  27. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

  28. Robson SC, Kaczmarek E, Siegel JB, Candinas D, Koziak K, Millan M, Hancock WW, Bach FH (1997) Loss of ATP diphosphohydrolase activity with endothelial cell activation. J Exp Med 185:153–163

  29. Schwiebert LM, Rice WC, Kudlow BA, Taylor AL, Schwiebert EM (2002) Extracellular ATP signaling and P2X nucleotide receptors in monolayers of primary human vascular endothelial cells. Am J Physiol Cell Physiol 282:C289–C301

  30. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276:125–132

  31. Tang L, Eaton JW (1999) Natural responses to unnatural materials: a molecular mechanism for foreign body reactions. Mol Med 5:351–358

  32. Tang L, Lucas AH, Eaton JW (1993) Inflammatory responses to implanted polymeric biomaterials: role of surface-adsorbed immunoglobulin G. J Lab Clin Med 122:292–300

  33. Turner CM, Vonend O, Chan C, Burnstock G, Unwin RJ (2003) The pattern of distribution of selected ATP-sensitive P2 receptor subtypes in normal rat kidney: an immunohistological study. Cells Tissues Organs 175:105–117

  34. Ventura MA, Thomopoulos P (1995) ADP and ATP activate distinct signaling pathways in human promonocytic U-937 cells differentiated with 1,25-dihydroxy-vitamin D3. Mol Pharmacol 47:104–114

  35. Vial C, Evans RJ (2002) P2X(1) receptor-deficient mice establish the native P2X receptor and a P2Y6-like receptor in arteries. Mol Pharmacol 62:1438–1445

  36. Vischer UM, Wollheim CB (1998) Purine nucleotides induce regulated secretion of von Willebrand factor: involvement of cytosolic Ca2+ and cyclic adenosine monophosphate-dependent signaling in endothelial exocytosis. Blood 91:118–127

  37. Wachem PB van, Luyn MJ van, Olde Damink LH, Dijkstra PJ, Feijen J, Nieuwenhuis P (1994) Biocompatibility and tissue regenerating capacity of crosslinked dermal sheep collagen. J Biomed Mater Res 28:353–363

  38. Woulfe D, Yang J, Brass L (2001) ADP and platelets: the end of the beginning. J Clin Invest 107:1503–1505

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The authors acknowledge L. Brouwer for her immunohistochemical evaluations.

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Correspondence to D. T. Luttikhuizen.

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Luttikhuizen, D.T., Harmsen, M.C., de Leij, L.F.M.H. et al. Expression of P2 receptors at sites of chronic inflammation. Cell Tissue Res 317, 289–298 (2004).

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  • Macrophages
  • Vasculature
  • Foreign body reaction
  • Purine
  • P2 receptor
  • Rat (AO, male)