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(American Journal of Pathology. 2004;164:1663-1672.)
© 2004 American Society for Investigative Pathology

Tumor Necrosis Factor- Induces Fractalkine Expression Preferentially in Arterial Endothelial Cells and Mithramycin A Suppresses TNF--Induced Fractalkine Expression

So Young Ahn^*, Chung-Hyun Cho^*, Keun-Gyu Park, Hyuek Jong Lee^*, Sik Lee, Sung Kwang Park, In-Kyu Lee and Gou Young Koh^*

From the Biomedical Research Center and Department of Biological Sciences,^* Korea Advanced Institute of Science and Technology, Daejeon; the Department of Internal Medicine, Keimyung University School of Medicine, Taegu; and the Department of Internal Medicine, Chonbuk National University Medical School, Chonju, Korea

Fractalkine is an unusual tumor necrosis factor (TNF)--induced chemokine. The molecule is tethered to cells that express it and produces strong and direct adhesion to leukocytes expressing fractalkine receptor. However, the potential mechanism and significance of TNF--induced fractalkine expression in vascular endothelial cells are poorly understood. Here we show that in primary cultured endothelial cells TNF--induced fractalkine mRNA expression is mediated mainly through phosphatidylinositol 3'-kinase activation and nuclear factor (NF)-B mediated transcriptional activation, along with GC-rich DNA-binding protein-mediated transcription. Interestingly, GC-rich DNA-binding protein inhibitors, mithramycin A and chromomycin A3, strongly suppressed TNF--induced fractalkine mRNA expression, possibly through inhibition of transcriptional activities by NF-B and Sp1. In fact, direct inhibition of NF-B and Sp1 bindings by decoy oligonucleotides suppressed TNF--induced fractalkine expression. Histologically, TNF--induced fractalkine expression was observed markedly in arterial and capillary endothelial cells, endocardium, and endothelium of intestinal villi, and slightly in venous endothelial cells, but not at all in lymphatic endothelial cells of intestine. Mithramycin A markedly suppressed TNF--induced fractalkine expression in vivo. These results indicate that TNF--stimulated fractalkine expression could act as part of arterial endothelial adhesion to leukocytes and monocytes during inflammation and atherosclerosis. NF-B and Sp1 inhibitors such as mithramycin A may provide a pharmacological approach to suppressing these processes.

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