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Published online before print April 9, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0204068

Received for publication February 3, 2004.
Revised March 1, 2004.
Accepted for publication March 9, 2004.

Article

Dexamethasone enhances LPS induction of tissue factor expression in human monocytic cells by increasing tissue factor mRNA stability

K. Veera Reddy ^*, Gourab Bhattacharjee ^*, Gernot Schabbauer ^*, Angela Hollis ^*, Kevin Kempf ^*, Michael Tencati ^*, Maria O’Connell , Mausumee Guha , and Nigel Mackman ^*@

*Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, California; MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom; and Isis Pharmaceuticals, Inc., Carlsbad Research Center, California

^@ To whom correspondence should be addressed. E-mail: nmackman{at}scripps.edu.

	Abstract

Glucocorticoids, such as dexamethasone (Dex), are used clinically in the treatment of various inflammatory diseases. Dex acts by inhibiting the expression of inflammatory mediators, such as tumor necrosis factor (TNF-) and monocyte chemoattractant protein-1 (MCP-1). It is surprising that Dex enhances bacterial lipopolysaccharide (LPS) induction of tissue factor (TF) expression in human monocytic cells. TF is a transmembrane glycoprotein that activates the coagulation protease cascade. In this study, we analyze the mechanism by which Dex enhances LPS-induced TF expression in human monocytic cells. We found that Dex reduced LPS-induced TF gene transcription but increased the stability of TF mRNA. Dex decreased the stability of MCP-1 mRNA and did not affect TNF- mRNA stability. Finally, we showed that Dex increased the stability of a transcript consisting of the final 297 nucleotides of the TF mRNA in in vitro decay assays. This region contains AU-rich elements that regulate mRNA stability and may mediate the Dex response. Therefore, despite an inhibition of TF gene transcription, Dex enhances TF expression in human monocytic cells by increasing the stability of TF mRNA.

Key Words: gene regulation • coagulation • glucocorticoid

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