Proinflammatory and prothrombotic effects on human vascular endothelial cells of Immune-cell-derived LIGHT

• Main Authors: Celik S, Shankar V, Richter A, Hippe H-J, Akhavanpoor M, Bea F, Erbel C, Urban S, Blank N, Wambsganss N, Katus HA, Dengler TJ
• Format: Article
• Language: English
• Published: BMC 2009-04-01
• Series: European Journal of Medical Research
• Subjects: LIGHT; endothelial cells; inflammation
• Online Access: http://www.eurjmedres.com/content/14/4/147

<p>Abstract</p> <p>Objective</p> <p>LIGHT (TNFSF 14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells as well as various types of antigen presenting cells. LIGHT binds to its cellular receptors TR2 and LTßR and has a co-stimulatory role in T cell activation. Here, we compared the relative expression of LIGHT in different immune cells and the biological activity of immune cell-derived LIGHT on endothelial cells.</p> <p>Methods and Results</p> <p>Surface expression of LIGHT and mRNA production by PBMC and isolated T cells (CD4⁺or CD8⁺) significantly increased after stimulation with PMA (Phorbolester-12-Myristat-13-Acetat) + ionomycin. No LIGHT expression on PMA stimulated monocytes or monocytic-like THP-1 cells could be detected; differentiation of monocytes and THP-1 cells into macrophages, however, resulted in up-regulation of LIGHT. Supernatants of stimulated T cells contained higher concentrations of soluble LIGHT than macrophage supernatants normalized to cell numbers; release of soluble LIGHT was found to be dependent on metalloproteinase activity. Size determination of released soluble LIGHT by size exclusion chromatography revealed a molecular mass of ~60 kDa, suggesting a trimeric form. Released soluble LIGHT induced expression of proinflammatory antigens ICAM-1, tissue factor and IL-8 in human endothelial cells and caused apoptosis of IFN-γ pretreated endothelial cells. Soluble LIGHT was detected at low levels in sera of healthy controls and was significantly enhanced in sera of patients with chronic hepatitis C and rheumatoid arthritis (24.93 ± 9.41 vs.129.53 ± 49.14 and 172.13 ± 77.64; p < 0.0005).</p> <p>Conclusion</p> <p>These findings suggest that among immune cells activated T lymphocytes are the main source of soluble LIGHT with released amounts of soluble LIGHT markedly higher compared to platelets. Immune cell-derived membrane-bound and soluble trimeric LIGHT is biologically active, inducing proinflammatory changes in endothelial cells. Enhanced plasma levels of soluble LIGHT in patients with chronic infections suggest a role of LIGHT in systemic inflammatory activation.</p>