Inflammatory Interaction Between LIGHT and Proteinase-Activated Receptor-2 in Endothelial Cells: Potential Role in Atherogenesis

• Published in: Circulation research 2009-01, Vol.104 (1), p.60-68
• Main Authors: Sandberg, Wiggo J, Halvorsen, Bente, Yndestad, Arne, Smith, Camilla, Otterdal, Kari, Brosstad, Frank R, Frøland, Stig S, Olofsson, Peder S, Damås, Jan K, Gullestad, Lars, Hansson, Göran K, Øie, Erik, Aukrust, Pål
• Format: Article
• Language: English
• Subjects: Aged; Angina Pectoris - metabolism; Angina Pectoris - pathology; Angina, Unstable - metabolism; Angina, Unstable - pathology; Animals; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured - metabolism; Chemokine CCL2 - secretion; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial Cells - secretion; Endothelium, Vascular - pathology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Humans; Interleukin-8 - secretion; JNK Mitogen-Activated Protein Kinases - physiology; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nitric Oxide Synthase Type III - metabolism; Receptor, PAR-2 - agonists; Receptor, PAR-2 - physiology; Receptors, Tumor Necrosis Factor, Member 14 - physiology; Recombinant Fusion Proteins - physiology; Signal Transduction - physiology; Tumor Necrosis Factor Ligand Superfamily Member 14 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 14 - physiology; Vasculitis - complications; Vasculitis - metabolism; Vasculitis - pathology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.188078

The interaction between inflammatory cytokines and endothelial cells is a critical step in atherogenesis leading to endothelial dysfunction and inflammation. We have previously reported that the tumor necrosis factor superfamily member LIGHT could be involved in atherogenesis through its ability to promote vascular inflammation. In the present study we identified proteinase-activated receptor (PAR)-2 as an inflammatory mediator that was markedly enhanced by LIGHT in endothelial cells. We also found that LIGHT acted synergistically with PAR-2 activation to promote enhanced release of the proatherogenic chemokines interleukin-8 and monocyte chemoattractant protein-1, underscoring that the interaction between LIGHT and PAR-2 is biologically active, promoting potent inflammatory effects. We showed that the LIGHT-mediated upregulation of PAR-2 in endothelial cells is mediated through the HVEM receptor, involving Jun N-terminal kinase signaling pathways. A LIGHT-mediated upregulation of PAR-2 mRNA levels was also found in human monocytes when these cells were preactivated by tumor necrosis factor α. We have previously demonstrated increased plasma levels of LIGHT in unstable angina patients, and here we show a similar pattern for PAR-2 expression in peripheral blood monocytes. We also found that LIGHT, LIGHT receptors, and PAR-2 showed enhanced expression, and, to some degree, colocalization in endothelial cells and macrophages, in the atherosclerotic plaques of ApoE mice, suggesting that the inflammatory interaction between LIGHT and PAR-2 also may be operating in vivo within an atherosclerotic lesion. Our findings suggest that LIGHT/PAR-2–driven inflammation could be a pathogenic loop in atherogenesis potentially representing a target for therapy in this disorder.