The Rho-GEF Trio regulates a novel pro-inflammatory pathway through the transcription factor Ets2
Jos Van Rijssel,
Ilse Timmerman,
Floris P. J. Van Alphen,
Mark Hoogenboezem,
Olexandr Korchynskyi,
Dirk Geerts,
Judy Geissler,
Kris A. Reedquist,
Hans W. M. Niessen,
Jaap D. Van Buul
Affiliations
Jos Van Rijssel
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, 1066CX, The Netherlands
Ilse Timmerman
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, 1066CX, The Netherlands
Floris P. J. Van Alphen
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, 1066CX, The Netherlands
Mark Hoogenboezem
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, 1066CX, The Netherlands
Olexandr Korchynskyi
Department of Cellular Proliferation and Apoptosis, Institute of Cell Biology, National Academy of Sciences of Ukraine, 79005 Lviv, Ukraine
Dirk Geerts
Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam 3015CE, The Netherlands
Judy Geissler
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1106CX, The Netherlands
Kris A. Reedquist
Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam 1105AZ, The Netherlands
Hans W. M. Niessen
Department of Pathology and Cardiac Surgery, ICaR-VU, VU University Medical Center, Amsterdam 1081HV, The Netherlands
Jaap D. Van Buul
Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, 1066CX, The Netherlands
Summary 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.
