Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Neurosignals 2012;20:86–102 DOI: 10.1159/000330805 JNK/ERK/FAK Mediate Promigratory Actions of Basic Fibroblast Growth Factor in Astrocytes via CCL2 and COX2 Mathieu P. Lichtenstein a, b José L.M. Madrigal f, g Aurora Pujol c–e Elena Galea a–c a Institut de Neurociències, b Departament de Bioquímica, Universitat Autònoma de Barcelona, c Institució Catalana de Recerca i Estudis Avançats, d Centre de Genètica Mèdica i Molecular, Institut d’Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Barcelona, e Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, f Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, y g Centro de Investigación Biomédica en Red de Salud Mental, Madrid, España ERK, JNK and FAK, and (iv) NF-  B-independent. FGF2 also caused accelerated wound closure dependent on CCL2, COX2, ERK, JNK and FAK in a scratch assay. We conclude that the signaling network triggered by FGF2 in astrocytes con- verged into accelerating directed motion. It follows that as- trocyte migration to injury sites may be a key factor in the repair mechanisms orchestrated by FGF2. Copyright © 2011 S. Karger AG, Basel Introduction Basic fibroblast growth factor (FGF2) is a ubiquitous and versatile peptide that regulates cell proliferation, mi- gration, cell survival and differentiation during develop- ment, tissue repair or tumor growth. FGF2 is produced in several isoforms ranging between 18 and 34 kDa that are produced by alternative use of two initiation codons at translation [1]. The low-molecular-weight (LMW) iso- form (18 kDa) is secreted [2, 3] by a mechanism implicat- ing multidrug resistance-associated proteins [4] and Na + / K + -ATPase [4, 5], and accounts for most of the biological functions attributed to FGF2 by acting through mem- brane-spanning tyrosine kinase receptors in conjunction with low-affinity binding to heparin sulfate proteogly- Key Words Astrocyte  Basic fibroblast growth factor  c-jun N-terminal kinase  Cytoskeleton  Extracellular-signal-regulated kinase  Focal adhesion kinase  Intercellular adhesion molecule migration  Monocyte chemoattractant protein  Cyclo-oxygenase-2 Abstract While the role of cytokines in causing pro- and anti-inflam- matory cascades in the brain and that of chemokines in pro- moting chemotaxis is well recognized, the immunomodula- tory actions of neurotrophins released during brain injury remains largely undetermined. This knowledge gap affects basic fibroblast growth factor (FGF2), which in the brain is mainly produced by astrocytes and characteristically upreg- ulated in reactive astrocytes. The goal of this study was to characterize the inflammatory actions of FGF2 in astrocytes using primary cultures. We report that FGF2 induced the up- regulation of monocyte chemoattractant protein (CCL2) and cyclo-oxygenase type 2 (COX2), and the inhibition of lipo- polysaccharide-elicited ICAM1 upregulation. The effects of FGF2 were: (i) dependent on gene transcription as revealed by the concomitant regulation of CCL2 or ICAM1 mRNAs; (ii) mediated by the FGF2 receptor type 2; (iii) dependent on Received: March 16, 2011 Accepted after revision: July 7, 2011 Published online: December 22, 2011 Mathieu P. Lichtenstein, MD Institut de Neurociències, Edifici M Universitat Autònoma de Barcelona, Bellaterra ES–08193 Barcelona (Spain) Tel. +34 93 586 8142, E-Mail matlichtenstein  @  hotmail.com © 2011 S. Karger AG, Basel 1424–862X/12/0202–0086$38.00/0 Accessible online at: www.karger.com/nsg Downloaded by: 54.89.179.252 - 11/21/2014 10:23:34 PM