Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium

Summary

LIGHT (TNFSF 14) belongs to the tumor necrosis factor super-family and is expressed by different types of immune cells. Recently, LIGHT was found to be associated with platelets and released upon activation. Activation of endothelial cells by recombinant LIGHT results in pro-inflammatory and pro-thrombotic changes, qualitatively comparable to effects of CD40 ligand. Given the important role of platelet-associated CD40 ligand in vascular inflammatory responses we investigated the role of LIGHT for activation of endothelium and adhesion of platelets to endothelial cells. Expression of LIGHT was detected on thrombocytes upon exposure to ADP or TRAP-1. The expression of the LIGHT receptors TR2 and LTβR on native human endothelial cells was confirmed by FACS analysis. LIGHT mediated adhesion of platelets to endothelium significantly, occurring both under static and dynamic flow conditions. This interaction was inhibited by a monoclonal antibody to LIGHT but not a control IgG. Moreover, in-vitro stimulation of endothelial cells with recombinant soluble human LIGHT (rhLIGHT) resulted in significantly increased transcriptional and translational upregulation of inflammatory markers ICAM-1, tissue factor (TF) and IL-8. This activation of endothelial cells by LIGHT was mediated by NFκB activation and qualitatively comparable to that induced by membrane-bound CD40-ligand on transfected cells. Furthermore, plasma levels of patients with myocardial infarction, in those with ST-elevation myocardial infarction (STEMI), showed increased plasma levels of LIGHT compared with healthy controls. In conclusion, platelet-associated LIGHT is involved in adhesion of platelets to endothelium while soluble LIGHT induces a pro-inflammatory state in vascular endothelial cells. LIGHT may thus be implicated in the pathogenesis of atherosclerosis and acute coronary syndrome, as evidenced by serum levels.

Keywords

Platelet adhesion - endothelial cells - inflammation

^* These authors contributed equally to this work.

^§ These authors contributed equally to this work.

• References

• 1 Mauri DN, Ebner R, Montgomery RI. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 1998; 8: 21-30.
• 2 Yu KY, Kwon B, Ni J. et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 1999; 274: 13733-13736.
• 3 Ruddle NH. Lymphoid neo-organogenesis: lymphotoxin’s role in inflammation and development. Immunol Res 1999; 19: 119-125.
• 4 Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487-501.
• 5 Zhai Y, Guo R, Hsu TL. et al. LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J Clin Invest 1998; 102: 1142-1151.
• 6 Browning JL, Miatkowski K, Sizing I. et al. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med 1996; 183: 867-878.
• 7 Ye Q, Fraser CC, Gao W. et al. Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival. J Exp Med 2002; 195: 795-800.
• 8 Bobik A, Kalinina N. Tumor necrosis factor receptor and ligand superfamily family members TNFRSF14 and LIGHT: new players in human atherogenesis. Arterioscler Thromb Vasc Biol 2001; 21: 1873-1875.
• 9 Scholz H, Sandberg W, Damas JK. et al. Enhanced plasma levels of LIGHT in unstable angina: possible pathogenic role in foam cell formation and thrombosis. Circulation 2005; 112: 2121-2129.
• 10 Chang YH, Hsieh SL, Chao Y. et al. Proinflammatory effects of LIGHT through HVEM and LTbetaR interactions in cultured human umbilical vein endothelial cells. J Biomed Sci 2005; 12: 363-375.
• 11 Otterdal K, Smith C, Oie E. et al. Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes. Blood 2006; 108: 928-935.
• 12 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
• 13 Langer H, Gawaz M. The role of platelets for the pathophysiology of acute coronary syndromes. Hamostaseologie 2006; 26: 114-118.
• 14 Gawaz M, Neumann FJ, Dickfeld T. et al. Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 1998; 98: 1164-1171.
• 15 Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
• 16 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61: 498-511.
• 17 Kaneider NC, Feistritzer C, Gritti D. et al. Expression and function of syndecan-4 in human platelets. Thromb Haemost 2005; 93: 1120-1127.
• 18 Gawaz M, Neumann FJ, Dickfeld T. et al. Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809-1818.
• 19 Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med 1998; 187: 329-339.
• 20 Langer H, May AE, Bultmann A. et al. ADAM 15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation. Thromb Haemost 2005; 94: 555-561.
• 21 Pober JS, Bevilacqua MP, Mendrick DL. et al. Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 1986; 136: 1680-1687.
• 22 Kluger MS, Johnson DR, Pober JS. Mechanism of sustained E-selectin expression in cultured human dermal microvascular endothelial cells. J Immunol 1997; 158: 887-896.
• 23 Langer H, May AE, Daub K. et al. Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res 2006; 98: e2-10.
• 24 Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 1998; 42: 477-484.
• 25 Viedt C, Hansch GM, Brandes RP. et al. The terminal complement complex C5b-9 stimulates interleukin- 6 production in human smooth muscle cells through activation of transcription factors NF-kappa B and AP-1. Faseb J 2000; 14: 2370-2372.
• 26 Lienenluke B, Germann T, Kroczek RA. et al. CD154 stimulation of interleukin-12 synthesis in human endothelial cells. Eur J Immunol 2000; 30: 2864-2870.
• 27 Klingenberg R, Autschbach F, Gleissner C. et al. Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro. Eur J Immunol 2005; 35: 1712-1721.
• 28 Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999; 138: S419-420.
• 29 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
• 30 Henn V, Steinbach S, Buchner K. et al. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 2001; 98: 1047-1054.
• 31 Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994; 76: 301-314.
• 32 Sachais BS. Platelet-endothelial interactions in atherosclerosis. Curr Atheroscler Rep 2001; 3: 412-416.
• 33 Babinska A, Azari BM, Salifu MO. et al. The F11 receptor (F11R/JAM-A) in atherothrombosis: overexpression of F11R in atherosclerotic plaques. Thromb Haemost 2007; 97: 272-281.
• 34 Aukrust P, Muller F, Ueland T. et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100: 614-620.