Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of inflammatory diseases. Excessive TNIF-alpha expresion induces tristetraprolin (UP), an RNA-binding protein that regulates mRNA degradation, which in turn downregulates TNF and its downstream genes, thus resulting in antiinflammatory effects. In order to better understand the TNF-alpha mediated molecular pathways in inflammatory diseases, embryonic fibroblast (MEF) cell lines derived from UP-deficient (KO) or wild type (WT) mice were treated with TNF-alpha and gene expression differences between two cell lines were compared by a microarray essay of 9224 genes. We found that UP-KO cells had higher expression levels of pro-inflammatory genes than UP-WT cells, and inflammatory genes were differentially regulated by TNF-alpha between UP-KO and UP-WT cells. Through a study of 2-dimentional gene set matrix analysis, we also found the genes upregulated by TNF-alpha in UP 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 UP in inflammatory pathways related to human diseases. (C) 2012 Elsevier Inc. All rights reserved.