A novel gene family induced by acute inflammation in endothelial cells

Abstract

The aim of this study was to characterise a novel family of inflammatory genes induced by pro-inflammatory cytokines in primary human endothelial cells. Using a genome-wide array screen two previously uncharacterised genes, NLF1 and NLF2 were identified that were upregulated over 30 fold by treatment with interleukin 1β for 2 h. They were also found to respond to tumour necrosis factor α, suggesting a general role in inflammation. Expression of both genes peaked 2 h after addition of interleukin 1β, with similar kinetics to the fastest nuclear factor κB (NF-κB) induced genes. The activation of both genes by interleukin 1β was abrogated by the proteasomal inhibitor, lactacystin which blocks activation of NF-κB by preventing IκB degradation. Furthermore, two sequences with homology to NF-κB binding sites in the promoter of NLF1 were found to be essential for rapid elevation in expression in response to interleukin 1β. NLF1 and NLF2 transcripts were found predominantly in endothelial cells, and the encoded proteins were localised to the nuclear compartment suggesting a role in the regulation of transcription. Transfection of recombinant NLF into endothelial cells resulted in upregulation of the Rho kinases, Rnd1 and Gem GTPase. We propose that NLF1 and NLF2 belong to a novel gene family encoding nuclear factors with a role in regulating genes which control cellular architecture. This might increase vascular permeability in acute inflammation. © 2004 Elsevier B.V. All rights reserved.