Role of RNA-binding protein tristetraprolin in tumor necrosis factor-α mediated gene expression

Abstract

Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis of inflammatory diseases. Excessive TNF-α expression induces tristetraprolin (TTP), an RNA-binding protein that regulates mRNA degradation, which in turn downregulates TNF and its downstream genes, thus resulting in anti-inflammatory effects. In order to better understand the TNF-α mediated molecular pathways in inflammatory diseases, embryonic fibroblast (MEF) cell lines derived from TTP-deficient (KO) or wild type (WT) mice were treated with TNF-α and gene expression differences between two cell lines were compared by a microarray essay of 9224 genes. We found that TTP-KO cells had higher expression levels of pro-inflammatory genes than TTP-WT cells, and inflammatory genes were differentially regulated by TNF-α between TTP-KO and TTP-WT cells. Through a study of 2-dimentional gene set matrix analysis, we also found the genes upregulated by TNF-α in TTP KO cells were correlated with the pathologic phenotypes in inflammation, joint, or bone diseases. Our study provided a detailed genetic roadmap for further understanding the regulatory effect of TTP in inflammatory pathways related to human diseases.