title: The Rho-GEF Trio regulates a novel pro-inflammatory pathway through the transcription factor Ets2.
abstract: Inflammation is characterized by endothelium that highly expresses numerous adhesion molecules to trigger leukocyte extravasation. Central to this event is increased gene transcription. Small Rho-GTPases not only control the actin cytoskeleton, but are also implicated in gene regulation. However, in inflammation, it is not clear how this is regulated. Here, we show that the guanine-nucleotide exchange factor Trio expression is increased upon inflammatory stimuli in endothelium. Additionally, increased Trio expression was found in the vessel wall of rheumatoid arthritis patients. Trio silencing impaired VCAM-1 expression. Finally, we excluded that Trio-controlled VCAM-1 expression used the classical NFκB or MAP-kinase pathways, but rather acts on the transcriptional level by increasing phosphorylation and nuclear translocalization of Ets2. These data implicate Trio in regulating inflammation and provide novel targets for therapeutic purposes to treat inflammatory diseases such as rheumatoid arthritis.
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam , Amsterdam, 1066CX , The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Van Rijssel
authors.forename: Ilse
authors.initials: I
authors.lastname: Timmerman
authors.forename: Floris P J
authors.initials: FP
authors.lastname: Van Alphen
authors.forename: Mark
authors.initials: M
authors.lastname: Hoogenboezem
authors.forename: Olexandr
authors.initials: O
authors.lastname: Korchynskyi
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Jaap D
authors.initials: JD
authors.lastname: Van Buul
keywords: Endothelium; GEF; GTPase; Inflammation; Signal transduction