Identification of genes selectively regulated by IFNs in endothelial cells

J Immunol. 2007 Jan 15;178(2):1122-35. doi: 10.4049/jimmunol.178.2.1122.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokines, CXC / metabolism
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics*
  • Humans
  • Interferons / pharmacology*
  • Kinetics
  • Male
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Receptors, CXCR3
  • Receptors, Chemokine / metabolism
  • Skin / blood supply
  • Skin / drug effects
  • Skin / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Umbilical Cord / metabolism

Substances

  • CXCL10 protein, human
  • CXCL11 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokines, CXC
  • Cxcl11 protein, mouse
  • Cxcr3 protein, mouse
  • RNA, Messenger
  • Receptors, CXCR3
  • Receptors, Chemokine
  • TNF-Related Apoptosis-Inducing Ligand
  • Interferons