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Scanu, Anna (2008) Il ruolo delle HDL nel controllo dell'infiammazione sinoviale. [Ph.D. thesis]

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Abstract (english)

Recent reports suggest that apolipoproteins (apo) exert an important role in controlling inflammation. It has been demonstrated that high density lipoprotein (HDL) are able to block the contact-mediated activation of monocytes-macrophages by stimulated T lymphocytes and inhibit the production of IL-1ß and TNF?.
Aim of the thesis: To investigate the effects of HDL on MCP-1 release from monosodium urate crystals-stimulated synoviocytes and IL-1ß, TNF? and IL-1Ra release from microparticles-stimulated monocytes.
Methods: Human synoviocytes were obtained by synovial tissue explants from patients with osteoarthritis and stimulated with monosodium urate (MSU) crystals (0.01-0.25 mg/ml) in the presence or absence of human HDL (50 e 100 ?g/ml).
Microparticles (MP) were isolated by ultracentrifugation from T lymphocytes and HUT-78 cultures stimulated with phorbol myristate acetate (PMA) (5 ng/ml) and phytohemagglutinin (PHA) (1 ?g/ml) for 48 and 6 h respectively. The cellular origin of MP was determined by flow cytometry. Human monocytes were activated for 48 h by MP from T lymphocytes at concentrations of 13.3 ?g/ml and 26.6 ?g/ml. HUT-78-derived MP were used at a concentration of 1.5-6 ?g/ml in the presence or absence of human HDL (0.2 mg/ml).
HDL were isolated from peripheral blood of healthy volunteers by ultracentrifugation.
MCP-1 was determined in cultured cells by western blotting and confocal microscopy, while the production of IL-1ß, TNF? and IL-1Ra was measured in culture supernatants by ELISA.
Results: Confocal microscopy and western blotting analysis revealed that MCP-1 resides in small cytoplasmatic granules on non stimulated cells. The exposure of synoviocytes to MSU crystals leads to a decrease of intracellular levels of the protein and an increase of extracellular chemokine concentration. The treatment of synoviocytes with HDL causes a dose-dependent inhibition of the release of MCP-1 which maintains its storage in granules. The same effect was observed pre-incubating cells with HDL 1 h before crystal activation.
MP generated by stimulated T cells induce a production of IL-1ß, TNF? and IL-1Ra in monocyte cultures higher than those obtained by MP from unstimulated T lymphocytes. It has also been observed that monocytes stimulated with MP generated by activated HUT-78 release IL-1ß, TNF? and IL-1Ra in a dose-dependent manner. The treatment with HDL inhibits IL-1ß and TNF? levels, whereas the production of IL-1Ra remains unchanged.
Conclusion: The inhibitory activity of HDL highlighted by the pre-treatment of cells is probably due to a direct action of lipoproteins on synoviocytes rather than to their adsorption on the surface of the crystals. By inhibiting MCP-1 release, HDL may limit the inflammatory process.
The production of cytokines depends on the activation level of cells from which MP take origin.
The almost complete inhibition of IL-1ß and TNF? levels by HDL lead us to hypothesize that HDL control cellular contact between MP and monocytes, as already observed in the lymphocytes T - monocytes interaction.

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EPrint type:Ph.D. thesis
Tutor:Punzi, Leonardo
Data di deposito della tesi:31 January 2008
Anno di Pubblicazione:31 January 2008
Key Words:HDL; cristalli di urato monosodico; microparticelle; infiammazione
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/16 Reumatologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Medicina Clinica e Sperimentale
Codice ID:697
Depositato il:09 Oct 2008
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1. Lawrence T, Willoughby DA, Gilroy DW. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2002;2:787–95. Cerca con Google

2. Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006; 24:823–35. Cerca con Google

3. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. Immunity 1998;8:297– 303. Cerca con Google

4. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001;11:372–7. Cerca con Google

5. Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res 2005;15:11–18. Cerca con Google

6. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002;109:S81–S96. Cerca con Google

7. Karin M. The regulation of AP-1 activity by mitogenactivated protein kinases. J Biol Chem 1995;270:16483–6. Cerca con Google

8. Martin M, Schifferle RE, Cuesta N, Vogel SN, Katz J, Michalek SM. Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J. Immunol. 2003;171:717–25. Cerca con Google

9. Oliviero F, Punzi L. L’infiammazione articolare da microcristalli. Reumatismo 2003;55:16–27. Cerca con Google

10. Rich AM, Giedd KN, Cristello P, Weissmann G. Granules are necessary for death of neutrophils after phagocytosis of crystalline monosodium urate. Inflammation 1985;9:221–32. Cerca con Google

11. Doherty M, Dieppe P. Crystal-related arthropathies. In: Rheumatology. Klippel JH, Dieppe PA eds, Mosby, London, 2000, 14.1–14. Cerca con Google

12. Terkeltaub R, , Zachariae C, Santoro D, Martin J, Peveri P, Matsushima K. Monocytederived neutrophil chemotactic factor/interleukin-8 is a potential mediator of crystalinduced inflammation. Arthritis Rheum 1991;34:894–903. Cerca con Google

13. Ryckman C, McColl SR, Vandal K, de Medicis R, Lussier A, Poubelle PE, et al. Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis. Arthritis Rheum 2003;48:2310–20. Cerca con Google

14. Jaramillo M, Godbout M, Naccache PH, Olivier M. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. J Biol Chem 2004;279:52797–805. Cerca con Google

15. Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology (Oxford) 2005;44:1090–6. Cerca con Google

16. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003;425:516–21. Cerca con Google

17. Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R. TLR2 signaling in chondrocytes drives calcium pyrophosphate dehydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 2005;174:5016–23. Cerca con Google

18. Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, et al. MyD88- dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 2006;116:2262–71. Cerca con Google

19. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. Cerca con Google

20. So A, De Smedt, Revaz S, Tschopp J. A pilot study on IL-1ß inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28. Cerca con Google

21. Ardoin SP, Shanahan JC, Pisetsky DS. The role of microparticles in inflammation and thrombosis. Scand J Immunol 2007;66:159–65. Cerca con Google

22. Martinez MC, Tesse A, Zobairi F, Andriantsitohaina R. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 2005;288:H1004–9. Cerca con Google

23. VanWijk MJ, VanBavelb E, Sturkc A, Nieuwland R. Microparticles in cardiovascular diseases. Card Res 2003;59:277–87. Cerca con Google

24. Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood 2007;21:157–71. Cerca con Google

25. Diaz C, Schroit AJ. Role of translocases in the generation of phosphatidylserine asymmetry. J Membr Biol 1996;151:1–9. Cerca con Google

26. Distler JHW, Pisetsky DS, Huber LC, Kalden JR, Gay S, Distler O. Arth Rheum 2005;52:3337–48. Cerca con Google

27. Hristov M, Erl W, Linder S, Weber PC. Apoptotic bodies from endothelial cells enhance the number and initiatethe differentiation of human endothelial progenitor cells in vitro. Blood 2004;104:2761–6. Cerca con Google

28. Gasser O, Hess C, Miot S, Deon C, Sanchez JC, Schifferli JA. Characterisation and properties of ectosomes released by human polymorphonuclear neutrophils. Exp Cell Res 2003;285:243–57. Cerca con Google

29. Fritzsching B, Schwer B, Kartenbeck J, Pedal A, Horejsi V, Ott M. Release and intercellular transfer of cell surface CD81 via microparticles. J Immunol 2002; 169:5531–7. Cerca con Google

30. Barry OP, Praticò D, Savani RC, FitzGerald GA. Modulation of Monocyte–Endothelial Cell Interactions by Platelet Microparticles. J Clin Invest 1998;102:136–44. Cerca con Google

31. Nauta AJ, Trouw LA, Daha MR, Tijsma1O, Nieuwland R, Schwaeble WJ, et al. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur J Immunol 2002;32:1726–36. Cerca con Google

32. Barry OP, Kazanietz MG, Praticò D, FitzGerald GA. Arachidonic Acid in Platelet Microparticles Up-regulates Cyclooxygenase-2-dependent Prostaglandin Formation via a Protein Kinase C/Mitogen-activated Protein Kinase-dependent Pathway. J Biol Chem 1999;274:7545–56. Cerca con Google

33. Mackenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A. Rapid Secretion of Interleukin-1ß by Microvesicle Shedding. Immunity 2001;8:825–35. Cerca con Google

34. Distler JHW, Huber LC, Hueber AJ, Reich III CF, Gay S, Distler O, et al. The release of microparticles by apoptotic cells and their effects on macrophages. Apoptosis 2005;10:731–41. Cerca con Google

35. Distler JHW, Jüngel A, Huber LC, Seemayer CA, Reich III CF, Gay RE, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc Natl Acad Sci USA 2005;102:2892– 7. Cerca con Google

36. Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 2003;28:284-93. Cerca con Google

37. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNF?-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 200;120:649–61. Cerca con Google

38. Alexander WS, Hilton DJ. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol 2004;22:503–29. Cerca con Google

39. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, et al. The ubiquitinmodifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 2004;5:1052–60. Cerca con Google

40. Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M. IKKß is required for prevention of apoptosis mediated by cell-bound but not by circulating TNF?. Immunity 2003;19:725–37. Cerca con Google

41. Nathan C. Points of control in inflammation. Nature 2002;420:846–52. Cerca con Google

42. Wells CA, Ravasi T, Hume DA. Inflammation suppressor genes: please switch out all the lights. J Leuk Biol 2005;78:9–13. Cerca con Google

43. Hurst SM, Wilkinson TS, McLoughlin RM, Jones S, Horiuchi S, Yamamoto N, et al. IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001;14:705–14. Cerca con Google

44. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2001;2:612–9. Cerca con Google

45. Huynh MN, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-_1 secretion and the resolution of inflammation. J Clin Invest 2002;109:41–50. Cerca con Google

46. Bellingan GJ, Xu P, Cooksley H, Cauldwell H, Shock A, Bottoms S, et al. Adhesion molecule–dependent mechanisms regulate the rate of macrophage clearance during the resolution of peritoneal inflammation. J Exp Med 2002;196:1515–21. Cerca con Google

47. Ariel A, Serhan CN. Resolvins and protectins in the termination program of acute inflammation. Trends Immunol 2007;28:176–83. Cerca con Google

48. Hyka N, Dayer JM, Modoux C, Kohno T, Edwards III CK, Roux-Lombard P, Burger D. Apolipoprotein A-I inhibits the production of interleukin-1b and tumor necrosis factor-a by blocking contact-mediated activation of monocytes by T lymphocytes Blood 2001;97:2381–9. Cerca con Google

49. Punzi L, Oliviero F, Dayer JM, Giunco S, Bernardi D, Plebani M, et al. Relationship between lipoproteins and synovial inflammation in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Clin Exp Rheum submitted. Cerca con Google

50. Cettour-Rose P, Nguyen TXK, Serrander L, Kaufmann MT, Dayer JM, Burger D, Roux-Lombard P. T cell contact-mediated activation of respiratory burst in human polymorphonuclear leukocytes is inhibited by highdensity lipoproteins and involves CD18. J Leukoc Biol 2005;77:52–8. Cerca con Google

51. Burger D, Dayer JM. High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation? Autoimmun Rev 2002;1:111-7. Cerca con Google

52. Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248– 54. Cerca con Google

53. Denko CW, Whitehouse MW. Experimental inflammation induced by natural occurring microcrystalline salts. J Rheumatol 1976;3:54. Cerca con Google

54. Burger D, Molnarfi N, Gruaz L, Dayer J M. Differential induction of IL-1beta and TNF by CD40 ligand or cellular contact with stimulated T cells depends on the maturation stage of human monocytes. J Immunol 2004;173:1292–1297. Cerca con Google

55. Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G, Garin J, et al. Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles. J Immunol 2001;166:7309–18. Cerca con Google

56. Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F, et al. In vitro generation of endothelial microparticles and possibile prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999;104:93–102. Cerca con Google

57. Boyum A. Separation of white blood cells. Nature 1964;204:793–4. Cerca con Google

58. Armant M, Rubio M, Delespesse G, Sarfati M. Soluble CD23 directly activates monocytes to contribute to the antigen-independent stimulation of resting T cells. J Immunol 1995;155:4868– 4875. Cerca con Google

59. Burger D. Cell contact-mediated signaling of monocytes by stimulated T cells: a major pathway for cytokine induction. Eur Cytokine Netw 2000;11:346–53. Cerca con Google

60. Brennan FM, Foey AD. Cytokine regulation in RA synovial tissue: role of T cell/macrophage contact-dependent interactions. Arthritis Res 2002; 4:S177–S182. Cerca con Google

61. Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:1987–94. Cerca con Google

62. Xia P, Vadas MA, Rye K-A, Barter PJ, Gamble JR. High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway: a possible mechanism for protection against atherosclerosis by HDL. J Biol Chem 1999;274:33143–7. Cerca con Google

63. Gomaraschi M, Basilico N, Sisto F, Taramelli D, Eligini S, Colli S, et al. High-density lipoproteins attenuate interleukin-6 production in endothelial cells exposed to proinflammatory stimuli. Biochim Biophys Acta 2005;1736:136–43. Cerca con Google

64. Watson A, Berliner J, Hama SY, La Du BN, Faull KF, Fogelman AM, et al. Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 1995;96:2882–91. Cerca con Google

65. Miyazaki A, Rahim AT, Ohta T, Morino Y, Horiuchi S. High density lipoprotein mediates selective reduction in cholesteryl esters from macrophage foam cells. Biochim Biophys Acta 1992;1126:73–80. Cerca con Google

66. Haas MJ, Horani M, Mreyoud A, Plummer B, Wong NC, Mooradian AD. Suppression of apolipoprotein AI gene expression in HepG2 cells by TNF alpha and IL-1beta. Biochim Biophys Acta 2003;1623:120–8. Cerca con Google

67. Chung CP, Avalos I, Raggi P, Stein CM. Atherosclerosis and inflammation: insights from rheumatoid arthritis. Clin Rheumatol 2007;26:1228–33. Cerca con Google

68. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebocontrolled trial. Lancet 2004;363:2015-21. Cerca con Google

69. Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, et al. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol 2007;34:1459-64. Cerca con Google

70. Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, et al. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 2004;109:3215-20. Cerca con Google

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