4th Annual BMRP Investigator Meeting - Abstract

Role of CREB Transcription Factors in Regulating Inflammatory Responses

Carrie M. Rosenberger^a, Mark Gilchrist, Bin Li, Vesteinn Thorsson and Alan A. Aderem

Institute for Systems Biology (Seattle, Washington, U.S.A.)

Macrophages initiate inflammation to combat infection.  However, the dysregulated production of inflammatory mediators can lead to chronic diseases such as inflammatory bowel disease.  We have used cDNA microarrays to define the transcriptional profile activated in primary macrophages by microbial products.  We have analyzed the data with a suite of computational tools to visualize and predict gene regulatory networks.  Hundreds of differentially expressed genes are regulated in successive waves of transcription.  We clustered the regulated genes according to their expression profiles and analyzed each gene cluster by MotifMogul software, which identified substantial overrepresentation of binding sites for CREB/ATF transcription factors in the regulatory DNA of particular gene clusters.  The CREB/ATF family of transcription factors consists of at least 14 proteins that share a consensus DNA binding sequence and a conserved basic leucine zipper DNA binding domain.  Using macrophages from knockout mice, we have confirmed computational predictions of the genes regulated by CREB family transcription factors following microbial stimulation by quantitative real-time PCR and microarray analysis.  Pro- and anti-inflammatory cytokine production was dysregulated in CREB-null macrophages.  We will be assessing the contribution of CREB-dependent transcription in inflammatory bowel disease models.

^aPrincipal Investigator