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* Istituto Oncologico Veneto, Padua, Italy;
Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;
Department of Oncology and Surgical Sciences, University of Padua, Padua, Italy;
Department of Molecular Genetics, University Eye Hospital, Tuebingen, Germany;
¶ Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy; and
|| Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Milan, Italy
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-
, IFN-
, or IFN-
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- in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN- 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- and IFN- 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--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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the Italian Association for Research on Cancer (AIRC), the Italian Foundation for Research on Cancer (FIRC), Ministero dell’Istruzione dell’Università e della Ricerca (MIUR; 60%) and Progetti di Rilevante Interesse Nazionale (PRIN; 40%), Ministero della Salute (Ricerca Finalizzata e Programma Straordinario per la Ricerca Oncologica), Fondo di Investimento per la Ricerca di Base (FIRB), Fondazione Cassa di Risparmio di Padova e Rovigo, Fondazione San Paolo; Comitato Interministeriale per la Programmazione Economica (CIPE)-Regione Liguria. L.A. is in the Degenerative Disease and Immunopathology Ph.D. program, University of Insubria.
2 Address correspondence and reprint requests to Dr. Alberto Amadori, Department. of Oncology and Surgical Sciences, University of Padua, Via Gattamelata, 64, I-35128 Padua, Italy. E-mail address: albido{at}unipd.it
3 Abbreviations used in this paper: EC, endothelial cell; GBP, guanylate-binding protein; HF, human primary fibroblast; HMVEC, human dermal microvascular EC; HMVAR, human renal macrovascular EC; VTH, vascular endothelial growth factor, TNF-, and heparin.
4 The online version of this article contains supplemental material.
5 A. A. and A. A. contributed equally to this study
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