title: Guanylate binding protein-1 inhibits spreading and migration of endothelial cells through induction of integrin alpha4 expression.
abstract: Human guanylate binding protein-1 (GBP-1) is a large GTPase that is induced by inflammatory cytokines and acts antiangiogenically through the inhibition of endothelial cell proliferation and migration. In this study, we detected that GBP-1-expressing cells show a significantly reduced spreading and migration on fibronectin matrices. Investigating possible mechanisms of these effects, we found that integrin alpha(4) (ITGA4) was consistently up-regulated at both the RNA and protein level in GBP-1-expressing cell cultures. Inhibition of cell spreading and migration by GBP-1 was dependent on the binding of ITGA4 to fibronectin. The inflammatory cytokines IL-1beta and TNF-alpha induced ITGA4 expression in HUVECs and inhibited spreading and migration. Knockdown of GBP-1 by shRNA abrogated inflammatory cytokine induced ITGA4 expression and restored spreading and migration capabilities of the cells. These results show that inhibition of endothelial cell spreading and migration by inflammatory cytokines is mediated by GBP-1 through induction of ITGA4 expression. Endothelial cell migration is a key process during angiogenesis. Therefore, ITGA4 may be a novel molecular target to modulate angiogenesis in human disease.
authors.affiliation: Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Weinländer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lehmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Paster
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
authors.forename: Christine
authors.initials: C
authors.lastname: Hohenadl
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D039441:Integrin alpha4 / Q000096:biosynthesis* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D005353:Fibronectins; C490287:GBP1 protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D039441:Integrin alpha4; D019204:GTP-Binding Proteins