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cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18

Genes & Immunity volume 5, pages 354–362 (2004)Cite this article

Abstract

We examine the effects of IL18 on monocytes by performing microarray experiments using cell line KG1. Based on sensitivity to IL18, we identified three functionally distinct gene expression clusters (EC). We see little proinflammatory gene induction at low IL18 concentrations, but instead observe induction of diverse NFκB signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NFκB. At the highest IL18 concentration, we observe a third gene cluster containing the proapoptotic Fas gene among others. Clustering of IL18-responsive genes based on cis-elements in their promoters agreed well with the ECs. We conclude that IL18 produces a dose-dependent transcriptional response that can in part be attributed to the composition of cis-elements in the promoters of IL18-responsive genes. These results also support a model for regulatory mechanisms that prevent spurious immune response due to weak cytokine fluctuations and a separate mechanism enabling induction of proinflammatory functions by higher levels of cytokine.

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Acknowledgements

We thank Tom Briggs for performing quantitative PCR reactions and Hamish Allen and Tariq Ghayur for critical reading of the manuscript. DL and ZW were partially funded by NIH Grant 1R01HG03110-01.

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Authors and Affiliations

  1. Bioinformatics Program, Boston University, Boston, MA, USA

    D Leyfer & Z Weng

  2. Abbott Bioresearch Center, Worcester, MA, USA

    A Bond, E Tworog, D Perron, S Maska, A Brito, J Kamens & J Voss

  3. Biomedical Engineering Department, Boston, MA, USA

    Z Weng

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  1. D Leyfer
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  2. A Bond
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Correspondence to J Voss.

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Supplementary Information accompanies the paper on Genes and Immunity's website (http://www.nature.com/gene).

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Leyfer, D., Bond, A., Tworog, E. et al. cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18. Genes Immun 5, 354–362 (2004). https://doi.org/10.1038/sj.gene.6364099

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  • DOI: https://doi.org/10.1038/sj.gene.6364099

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