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TC1(C8orf4) Is a Novel Endothelial Inflammatory Regulator Enhancing NF-B Activity¹

Jungtae Kim^*, Yunlim Kim, Hyun-Taek Kim, Dong Wook Kim^*, Yunhi Ha, Jihun Kim, Cheol-Hee Kim, Inchul Lee^2, and Kyuyoung Song^2,

^* Asan Institute for Life Sciences, and Departments of Biochemistry and Molecular Biology and Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; and Department of Biology and GRAST, Chungnam National University, Daejeon, Korea

Endothelial inflammation is regulated by a complex molecular mechanism. TC1(C8orf4) is a novel regulator implicated in cancer and inflammation. It is a small protein conserved well among vertebrates. In zebrafish embryos, it is mostly expressed in angio-hematopoietic system and the overexpression induces edema. In human aortic endothelial cells and umbilical vein endothelial cells, TC1 transfection up-regulates key inflammatory cytokines, enzymes, and adhesion proteins including IL-6, IL-1, COX-2, CXCL1, CCL5, CCL2, IL-8, ICAM1, VCAM1, and E-selectin, while TC1 knockdown down-regulates them. TC1 also enhances inflammatory parameters such as monocyte-endothelial adhesion and endothelial monolayer permeability. TC1 is up-regulated by IL-1β, TNF-, LPS, and phorbol ester, and the up-regulation is inhibited by I-B-kinase inhibitors. TC1, in turn, enhances the nuclear translocation of RelA and the DNA binding activity, suggesting a biological role of amplifying NF-B signaling via a positive feedback. Our findings suggest that TC1 is a novel endothelial inflammatory regulator that might be implicated in inflammatory vascular diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Research Program for New Drug Target Discovery (M10748000294-08N4800-29410 to I.L.) and the Core Research program (R01-2008-000-11296-0 to K.S.) Grants of Korea Science and Engineering Foundation from the Ministry of Education, Science, and Technology, Korea.

² Address correspondence and reprint requests to Inchul Lee or Kyuyoung Song, Departments of Pathology and Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Poongnap-Dong, Songpa-Gu, Seoul. E-mail address: iclee{at}amc.seoul.kr or kysong{at}amc.seoul.kr

³ Abbreviations used in this paper: HAEC, human aortic endothelial cell; HUVEC, human umbilical vein endothelial cell; TPA, 12-O-tetradecanoylphorbol-13-acetate; EGCG, epigallocatechin-3-O-gallate; IKK, I-B-kinase.

⁴ The online version of this article contains supplemental material.