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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:2004.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Tumor Necrosis Factor Receptor Superfamily 14 Is Involved in Atherogenesis by Inducing Proinflammatory Cytokines and Matrix Metalloproteinases

Won-Ha Lee; Se-Hwa Kim; Yoon Lee; Byung Boong Lee; Byungsuk Kwon; Hebok Song; Byoung S. Kwon; Jeong-Euy Park

From the Cardiology Division (W.-H.L., S.-H.K., Y.L., J.-E.P.) and the Division of Vascular Surgery (B.B.L.), Sungkyunkwan University School of Medicine, Seoul, Korea; the Immunomodulation Research Center (B.K., H.S., B.S.K.), University of Ulsan, Korea; Pennington Biomedical Research Center (W.-H.L.), Louisiana State University, Baton Rouge; and the Department of Ophthalmology (B.S.K.), Louisiana State University Health Science Center, New Orleans.

Correspondence to Byoung S. Kwon, PhD, Department of Ophthalmology, LSUHSC, New Orleans, LA 70112, or Jeong-Euy Park, MD, Cardiology Division, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong Kangnam-Ku, Seoul 135-710, Korea. E-mail bskwon{at}uou.ulsan.ac.kr or jepark@smc.samsung.co.kr

Tumor necrosis factor (TNF) receptor superfamily 14 (TNFRSF14) is the cellular receptor for TNF superfamily 14 (LIGHT). Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high level of expression of the TNFRSF14 in regions rich in macrophages/foam cells. To investigate the role of TNFRSF14 in the functioning of monocytes in relation to atherogenesis, we have analyzed TNFRSF14 expression levels and cellular events after stimulation of TNFRSF14 in peripheral blood monocytes or the human macrophage–like cell line, THP-1. A high level of expression of TNFRSF14 was detected in activated monocytes, in macrophages derived from monocytes, and in THP-1 cells. Concomitant activation of THP-1 cells with interferon- and immobilized anti-TNFRSF14 monoclonal antibody resulted in synergistic induction of proatherogenic cytokines, such as TNF- and interleukin-8. Activation of THP-1 cells with immobilized anti-TNFRSF14 monoclonal antibody induced expression of matrix metalloproteinase (MMP)-1, MMP-9, MMP-13, and tissue inhibitors of metalloproteinase-1 and -2. Furthermore, immunohistochemical staining of atherosclerotic plaques with severe infiltration of foam cells revealed that the expression patterns of TNFRSF14 and MMP-1, -9, and -13 overlapped. Treatment of THP-1 cells with soluble LIGHT also caused induction of MMP-9 and interleukin-8. These data suggest that TNFRSF14 is involved in atherosclerosis via the induction of proatherogenic cytokines and decreasing plaque stability by inducing extracellular matrix–degrading enzymes.

Key Words: atherosclerosis • immunity • tumor necrosis factor receptor superfamily 14 • matrix metalloproteinases • foam cells

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