The Journal of Experimental Medicine
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Published online 5 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/9/695/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 695-704

Original Article

Inhibition of E-Selectin Gene Expression by Transforming Growth Factor β in Endothelial Cells Involves Coactivator Integration of Smad and Nuclear Factor {kappa}B–Mediated Signals

Maria R. DiChiaraa, Jeanne Marie Kielyb, Michael A. Gimbrone, Jr.b, Mu-En Leec, Mark A. Perrellad, and James N. Toppera,e

a Cardiovascular Division, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305
b Vascular Research Division, Department of Pathology
c Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115
d Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115
e COR Therapeutics, Incorporated, South San Francisco, California 94080
COR Therapeutics, Inc., 256 E. Grand Ave., South San Francisco, CA 94080.650-244-9270650-244-7333

jtopper{at}corr.com

Transforming growth factor (TGF)-β1 is a pleiotropic cytokine/growth factor that is thought to play a critical role in the modulation of inflammatory events. We demonstrate that exogenous TGF-β1 can inhibit the expression of the proinflammatory adhesion molecule, E-selectin, in vascular endothelium exposed to inflammatory stimuli both in vitro and in vivo. This inhibitory effect occurs at the level of transcription of the E-selectin gene and is dependent on the action of Smad proteins, a class of intracellular signaling proteins involved in mediating the cellular effects of TGF-β1. Furthermore, we demonstrate that these Smad-mediated effects in endothelial cells result from a novel competitive interaction between Smad proteins activated by TGF-β1 and nuclear factor {kappa}B (NF{kappa}B) proteins activated by inflammatory stimuli (such as cytokines or bacterial lipopolysaccharide) that is mediated by the transcriptional coactivator cyclic AMP response element–binding protein (CREB)-binding protein (CBP). Augmentation of the limited amount of CBP present in endothelial cells (via overexpression) or selective disruption of Smad–CBP interactions (via a dominant negative strategy) effectively antagonizes the ability of TGF-β1 to block proinflammatory E-selectin expression. These data thus demonstrate a novel mechanism of interaction between TGF-β1–regulated Smad proteins and NF{kappa}B proteins regulated by inflammatory stimuli in vascular endothelial cells. This type of signaling mechanism may play an important role in the immunomodulatory actions of this cytokine/growth factor in the cardiovascular system.

Key Words: inflammation • transcription • transforming growth factor • vascular biology • endothelium

Abbreviations used in this paper: BAEC, bovine aortic endothelial cell; CBP, cyclic AMP response element–binding protein (CREB)-binding protein; HUVEC, human umbilical vein endothelial cell; NF{kappa}B, nuclear factor {kappa}B.

© 2000 The Rockefeller University Press


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