title: Identification of genes selectively regulated by IFNs in endothelial cells.
abstract: IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-alpha, IFN-beta, or IFN-gamma were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-alpha in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-alpha in EC along with other genes associated with angiogenesis regulation, including CXCL10, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-alpha and IFN-beta exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-alpha-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.
authors.affiliation: Department of Oncology and Surgical Sciences, Istituto Oncologico Veneto, Via Gattemelata 64, I-35128 Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.forename: Sonia
authors.initials: S
authors.lastname: Minuzzo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Valeria
authors.initials: V
authors.lastname: Roni
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ferrari
authors.forename: Luca
authors.initials: L
authors.lastname: Anfosso
authors.forename: Raffaella
authors.initials: R
authors.lastname: Dell'Eva
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Noonan
authors.forename: Luigi
authors.initials: L
authors.lastname: Chieco-Bianchi
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014470:Umbilical Cord / Q000378:metabolism
chemical_list: C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D053221:TNF-Related Apoptosis-Inducing Ligand; D007372:Interferons