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First published online September 19, 2007
doi: 10.1242/10.1242/jcs.007872

Journal of Cell Science 120, 3352-3361 (2007)
Published by The Company of Biologists 2007
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Research Article

Notch3 and IL-1beta exert opposing effects on a vascular smooth muscle cell inflammatory pathway in which NF-{kappa}B drives crosstalk

Nathalie Clément1,*, Marie Gueguen1,*, Martine Glorian1, Régis Blaise1,2, Marise Andréani1, Christel Brou2, Pedro Bausero1 and Isabelle Limon1,{ddagger}

1 UMR 7079 de Physiologie et Physiopathologie, Université Pierre et Marie Curie, CNRS, 7 quai Saint-Bernard, 75252 Paris, France
2 Unité de Signalisation Moléculaire et Activation Cellulaire, URA 2582, CNRS, Institut Pasteur, 75724 Paris Cedex 15, France

{ddagger} Author for correspondence (e-mail: Isabelle.Limon-Boulez{at}snv.jussieu.fr)

Accepted 20 July 2007

Atherogenesis begins with the transfer of monocytes from the lumen to the intimal layer of arteries. The paracrine activity acquired by these monocytes shifts vascular smooth muscle cells from a contractile-quiescent to a secretory-proliferative phenotype, allowing them to survive and migrate in the intima. Transformed and relocated, they also start to produce and/or secrete inflammatory enzymes, converting them into inflammatory cells. Activation of the Notch pathway, a crucial determinant of cell fate, regulates some of the new features acquired by these cells as it triggers vascular smooth muscle cells to grow and inhibits their death and migration. Here, we evaluate whether and how the Notch pathway regulates the cell transition towards an inflammatory or de-differentiated state. Activation of the Notch pathway by the notch ligand Delta1, as well as overexpression of the active form of Notch3, prevents this phenomenon [initiated by interleukin 1beta (IL-1beta)], whereas inhibiting the Notch pathway enhances the transition. IL-1beta decreases the expression of Notch3 and Notch target genes. As shown by using an I{kappa}B{alpha}-mutated form, the decrease of Notch3 signaling elements occurs subsequent to dissociation of the NF-{kappa}B complex. These results demonstrate that the Notch3 pathway is attenuated through NF-{kappa}B activation, allowing vascular smooth muscle cells to switch into an inflammatory state.

Key words: Vascular smooth muscle cells, Notch, Inflammation




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