LIGHT is Expressed in Foam Cells and Involved in Destabilization of Atherosclerotic Plaques through Induction of Matrix Metalloproteinase-9 and IL-8

ABSTRACT

BACKGROUND: LIGHT (TNFSF14) is a member of tumor necrosis factor superfamily and is the ligand for TR2 (TNFRSF14/HVEM). LIGHT is known to have pro- inflammatory roles in atherosclerosis. METHODS: To find out the expression pattern of LIGHT in atherosclerotic plaques, immunohistochemical analysis was performed on human carotid atherosclerotic plaque specimens. LIGHT induced atherogenic events using human monocytic cell line THP-1 were also investigated. RESULTS: Immunohistochemical analysis revealed expression of LIGHT and TR2 in foam cell rich regions in the atherosclerotic plaques. Double immunohistochemical analysis further confirmed the expression of LIGHT in foam cells. Stimulation of THP-1 cells, which express TR2, with either recombinant LIGHT or immobilized anti-TR2 monoclonal antibody induced interleukin-8 and matrix metalloproteinase(MMP)-9. Electrophoretic mobility shift assay demonstrated that LIGHT induces nuclear localization of transcription factor, nuclear factor (NF)-kappaB. LIGHT induced activation of MMP-9 is mediated by NF-kappaB, since treatment of THP-1 cells with the NF-kappaB inhibitor PDTC (pyrrolidine dithiocarbamate) completely blocked the activation of MMP-9. CONCLUSION: These data indicate that LIGHT is expressed in foam cells in atherosclerotic plaques and is involved in atherogenesis through activation of pro-atherogenic cytokine IL-8 and destabilization of plaque by inducing matrix degrading enzyme.