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Platelet-activating factor and oxidized phosphatidylcholines do not suppress endotoxin-induced pro-inflammatory signaling among human myeloid and endothelial cells

1 Department of Studies in Biochemistry and Molecular biology, University of Mysore, Manasagangothri, Mysuru-570006, Karnataka, India
2 Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
3 Division of Allergy and Immunology, University of Utah, 81 N Mario Capecchi Drive, Salt Lake City, Utah 84113, USA
4 Department of Physiology and Pharmacology, Health Science Campus, Block health Science Building, 3000 Transverse Drive, Toledo, Ohio 43614, USA

Platelet-activating factor (PAF) and related phospholipid oxidation products termed oxidized phospholipids (OxPLs) promote inflammation. PAF is made in response to bacterial endotoxin-lipopolysaccharide (LPS) that is recognized by Toll-like receptor-4 (TLR-4) whose activation leads to translocation of transcription factor NF-ΚB to the nucleus—a key regulator of multiple pro-inflammatory genes including COX-2 and IL-8. Paradoxically, PAF and OxPLs are claimed to inhibit LPS-mediated signaling, questioning the very pro-inflammatory roles of PAF and OxPLs and anti-inflammatory nature of PAF-acetylhydrolase (PAF-AH), an enzyme that attenuates both PAF and OxPLs signaling. We investigated the effect of PAF and representative OxPLs: 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl-sn- glycero-3-phosphocholine (PGPC) and 1-alkyl-2-butanoyl-sn-glycero-3-phosphocholine PAF (C4 PAF) on LPS-induced expression of NF-ΚB mediated inflammation in isolated human myeloid cells: polymorphonuclear leukocyte (PMNs), monocytes and human umbilical vein endothelial cells (HUVECs). Using intracellular calcium transients, we show that POVPC and PGPC dose-dependently activate the PAF-receptor (PAF-R) in PMNs, that can beblocked by the PAF-R antagonist WEB-2086 and rPAF-AH pre-treatment. All the three cell types express minute or no detectable COX-2 when stimulated with either PAF (0.1 µM) or OxPLs (0.1 µM) alone. While LPS (100 ng/mL) induced expression of COX-2 in all the cell types, pre-activation of PAF-R with PAF (0.1 µM) or OxPLs (0.1 µM) did not suppress LPS (100 ng/mL)-induced COX-2 expression and in fact we obresved incereased PGE2 levels in an NS-398 sensitive manner. In addition, pre-activation of PAF-R significantly augmented LPS (100 ng/mL)-induced IL-8 production in PMNs. Thus, PAF and OXPLs do not suppress the ability of LPS to exert its pro-inflammatory effects in isolated human vascular cells.
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References

1. Zimmerman GA, Lorant DE, McIntyre TM, et al. (1993) Juxtacrine intercellular signaling: another way to do it. Am J Resp Cell Mol Biol 9: 573–577.    

2. Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71: 635–700.    

3. Beutler B, Rietschel ET (2003) Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 3: 169–176.    

4. Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1: 135–145.    

5. Hoffmann A, Baltimore D (2006) Circuitry of nuclear factor kappa B signaling. Immunol Rev 210: 171–186.    

6. Oeckinghaus A, Ghosh S (2009) The NF-kappa B family of transcription factors and its regulation. CSH Perspect Biol 1: a000034.

7. Weyrich AS, McIntyre TM, McEver RP, et al. (1995) Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest 95: 2297–2303.

8. Yost CC, Weyrich AS, Zimmerman GA (2010) The platelet-activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 92: 692–697.    

9. Brand K, Page S, Walli AK, et al. (1997) Role of nuclear factor‐kappa B in atherogenesis. Exp Physiol 82: 297–304.    

10. Baker RG, Hayden MS, Ghosh S (2011) NF-kappa B, inflammation and metabolic disease. Cell Metab 13: 11–22.    

11. Prescott SM, Zimmerman GA, Stafforini DM, et al. (2000) Platelet-activating factor and related lipid mediators. Annu Rev Biochem 69: 419–445.    

12. Mozes T, Heiligers JP, Tak CJ, et al. (1991) Platelet-activating factor is one of the mediators involved in endotoxic shock in pigs. J lipid Med 4: 309–325.

13. Koltai M, Hosford D, Braquet P (1993) PAF-induced amplification of mediator release in septic shock: prevention or downregulation by PAF antagonists. J Lipid Med 6: 183–198.

14. Shimizu T, Honda Z, Nakamura M, et al. (1992) Platelet-activating factor receptor and signal transduction. Biochem Pharmacol 44: 1001–1008.    

15. Marathe GK, Davies SS, Harrison KA, et al. (1999) Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J Biol Chem 274: 28395–28404.    

16. Marathe GK, Harrison KA, Murphy RC, et al. (2000) Bioactive phospholipid oxidation products. Free Radical Biol Med 28: 1762–1770.

17. Smiley PL, Stremler KE, Prescott SM, et al. (1991) Oxidatively fragmented phosphatidylcholines activate human neutrophils through the receptor for platelet-activating factor. J Biol Chem 266: 11104–11110.

18. Marathe GK, Prescott SM, Zimmerman GA, et al. (2001) Oxidized LDL contains inflammatory PAF-like phospholipids. Trends Cardiovas Med 11: 139–142.    

19. Leitinger N, Watson AD, Faull KF, et al. (1997) Monocyte binding to endothelial cells induced by oxidized phospholipids present in minimally oxidized low density lipoprotein is inhibited by a platelet-activating factor receptor antagonist. Adv Expt Med Biol 433: 379–382.    

20. Chen R, Chen X, Salomon RG, et al. (2009) Platelet activation by low concentrations of intact oxidized LDL particles involves the PAF receptor. Arterioscl Throm Vas Biol 29: 363–371.    

21. Subbanagounder G, Leitinger N, Shih PT, et al. (1999) Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis: in vitro and in vivo inhibition by WEB-2086. Circ Res 85: 311–318.    

22. Knapp S, Matt U, Leitinger N, et al. (2007) Oxidized phospholipids inhibit phagocytosis and impair outcome in Gram-negative sepsis in vivo. J Immunol 178: 993–1001.    

23. Marathe GK, Pandit C, Lakshmikanth CL, et al. (2014) To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase. J Lipid Res 55: 1847–1854.    

24. Watson AD, Leitinger N, Navab M, et al. (1997) Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/ endothelial interactions and evidence for their presence in vivo. J Biol Chem 272: 13597–13607.    

25. Steinberg D, Parthasarathy S, Carew TE, et al. (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. New Engl J Med 320: 915–924.

26. Berliner JA, Heinecke JW (1996) The role of oxidized lipoproteins in atherogenesis. Free Radical Bio Med 20: 707–727.    

27. Yla-Herttuala S, Palinski W, Rosenfeld ME, et al. (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 84: 1086–1095.    

28. Yang L, Latchoumycandane C, McMullen MR, et al. (2010) Chronic alcohol exposure increases circulating bioactive oxidized phospholipids. J Biol Chem 285: 22211–22220.    

29. Lehr HA, Weyrich AS, Saetzler RK, et al. (1997) Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking. J Clin Invest 99: 2358–2364.    

30. Appleyard CB, Hillier K (1995) Biosynthesis of platelet-activating factor in normal and inflamed human colon mucosa: evidence for the involvement of the pathway of platelet- activating factor synthesis denovo in inflammatory bowel disease. Clin Sci 88: 713–717.    

31. Marathe GK, Johnson C, Billings SD, et al. (2005) Ultraviolet B radiation generates platelet-activating factor-like phospholipids underlying cutaneous damage. J Biol Chem 280: 35448–35457.    

32. Stafforini DM (2009) Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc Drug Ther 23: 73–83.    

33. Bochkov VN, Philippova M, Oskolkova O, et al. (2006) Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions. Circ Res 99: 900–908.    

34. Silva AR, de Assis EF, Caiado LF, et al. (2002) Monocyte chemoattractant protein-1 and 5-lipoxygenase products recruit leukocytes in response to platelet-activating factor-like lipids in oxidized low-density lipoprotein. J Immunol 168: 4112–4120.    

35. Pontsler AV, StHilaire A, Marathe GK, et al. (2002) Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein. J Biol Chem 277: 13029–13036.    

36. Ricote M, Huang J, Fajas L, et al. (1998) Expression of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. P Natl Acad Sci USA 95: 7614–7619.

37. Schonbeck U, Sukhova GK, Graber P, et al. (1999) Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 155: 1281–1291.    

38. Marathe GK, Zimmerman GA, Prescott SM, et al. (2002) Activation of vascular cells by PAF-like lipids in oxidized LDL. Vasc Pharmacol 38: 193–200.    

39. Latchoumycandane C, Marathe GK, Zhang R, et al. (2012) Oxidatively truncated phospholipids are required agents of tumor necrosis factor alpha (TNF alpha)-induced apoptosis. J Biol Chem 287: 17693–17705.    

40. Bochkov VN, Kadl A, Huber J, et al. (2002) Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 419: 77–81.    

41. Jeong YI, Jung ID, Lee CM, et al. (2009) The novel role of platelet-activating factor in protecting mice against lipopolysaccharide-induced endotoxic shock. PLoS One 4: e6503.    

42. Eligini S, Brambilla M, Banfi C, et al. (2002) Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-kappa B/I kappa B and ERK2-dependent mechanisms. Cardiovasc Res 55: 406–415.    

43. Oskolkova OV, Afonyushkin T, Preinerstorfer B, et al. (2010) Oxidized phospholipids are more potent antagonists of lipopolysaccharide than inducers of inflammation. J Immunol 185: 7706–7712.    

44. Zimmerman GA, Renzetti AD, Hill HR (1984) Granulocyte adherence in pulmonary and systemic arterial blood samples from patients with adult respiratory distress syndrome. Am Rev Respir Dis 129: 798–804.    

45. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular and molecularbiology. Annu Rev Biochem 69: 145–182.    

46. Herschman HR (1996) Prostaglandin synthase 2. Biochim Biophys Acta 1299: 125–140.    

47. Maloney CG, Kutchera WA, Albertine KH, et al. (1998) Inflammatory agonists induce cyclooxygenase type 2 expression by human neutrophils. J Immunol 160: 1402–1410.

48. Marnett LJ, Rowlinson SW, Goodwin DC, et al. (1999) Arachidonic acid oxygenation by COX-1 and COX-2 Mechanisms of catalysis and inhibition. J Biol Chem 274: 22903–22906.    

49. Hoffmann E, Dittrich-Breiholz O, Holtmann H, et al. (2002) Multiple control of interleukin-8 gene expression. J Leukocyte Biol 72: 847–855.

50. Countryman NB, Pei Y, Yi Q, et al. (2000) Evidence for involvement of the epidermal platelet-activating factor receptor in ultraviolet-B-radiation-induced interleukin-8 production. J Invest Dermatol 115: 267–272.    

51. Yost CC, Denis MM, Lindemann S, et al. (2004) Activated polymorphonuclear leukocytes rapidly synthesize retinoic acid receptor-alpha: a mechanism for translational control of transcriptional events. J Exp Med 200: 671–680.    

52. Matt U, Sharif O, Martins R, et al. (2015) Accumulating evidence for a role of oxidized phospholipids in infectious diseases. Cell Mol Life Sci 72: 1059–1071.    

53. Mathiak G, Szewczyk D, Abdullah F, et al. (1997) Platelet-activating factor (PAF) in experimental and clinical sepsis. Shock 7: 391–404.    

54. Fukuda Y, Kawashima H, Saito K, et al. (2000) Effect of human plasma-type platelet-activating factor acetylhydrolase in two anaphylactic shock models. Eur J Pharmacol 390: 203–207.    

55. Giral M, Balsa D, Ferrando R, et al. (1996) Effects of UR-12633, a new antagonist of platelet-activating factor, in rodent models of endotoxic shock. Brit J Pharmacol 118: 1223–1231.    

56. Suckling KE, Macphee CH (2002) Lipoprotein-associated phospholipase A2: a target directed at the atherosclerotic plaque. Expert Opin Ther Tar 6: 309–314.    

57. Mullard A (2014) GSK's darapladib failures dim hopes for anti-inflammatory heart drugs. Nat Rev Drug Discov 13: 481–482.    

58. Riedemann NC, Ward PA (2002) Oxidized lipid protects against sepsis. Nat Med 8: 1084–1085.    

59. Matt U, Sharif O, Martins R, et al. (2013) WAVE 1 mediates suppression of phagocytosis by phospholipid-derived DAMPs. J Clin Invest 123: 3014–3024.    

60. Jacob SP, Lakshmikanth CL, Chaithra VH, et al. (2016) Lipopolysaccharide cross-tolerance delays platelet-activating factor induced sudden death in Swiss albino mice: involvement of cyclooxygenase in cross- tolerance. PLoS One: e0153282.

61. Leitinger N, Tyner TR, Oslund L, et al. (1999) Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. P Natl Acad Sci USA 96: 12010–12015.

62. Watanabe J, Marathe GK, Neilsen PO, et al. (2003) Endotoxins stimulate neutrophil adhesion followed by synthesis and release of platelet-activating factor in microparticles. J Biol Chem 278: 33161–33168.    

63. Stafforini DM, Elstad MR, McIntyre TM, et al. (1990) Human macrophages secret platelet-activating factor acetylhydrolase. J Biol Chem 265: 9682–9687.

64. Uhlson C, Harrison K, Allen CB, et al. (2002) Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability. Chem Res Toxicol 15: 896–906.    

65. Dahl M, Bauer AK, Arredouani M, et al. (2007) Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II. J Clin Invest 117: 757–764.    

66. Podrez EA, Febbraio M, Sheibani N, et al. (2000) Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 105: 1095–1108.    

67. Chen M, Masaki T, Sawamura T (2002) LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Therapeut 95: 89–100.    

68. Teixeira-da-Cunha MG, Gomes RN, Roehrs N, et al. (2013) Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. PLoS One 8: e74567.    

69. Chen CH, Jiang T, Yang JH, et al. (2003) Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation 107: 2102–2108.    

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