1. ¹Bioinformatics Program, Boston University, Boston, MA, USA
2. ²Abbott Bioresearch Center, Worcester, MA, USA
3. ³Biomedical Engineering Department, Boston, MA, USA

Correspondence: Dr J Voss, Abbott Bioresearch Center, Worcester, MA 01605, USA. E-mail: jeffrey.voss@abbott.com

Received 12 January 2004; Revised 22 March 2004; Accepted 22 March 2004; Published online 10 June 2004.

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 NFB signaling inhibitors. Conversely, intermediate concentrations of IL18 induced proinflammatory genes including the activating subunits of NFB. 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.