Severe Impairment of TNF Post-transcriptional Regulation Leads to Embryonic Death

Post-transcriptional regulation mechanisms control mRNA stability or translational efficiency via ribosomes, and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. Transcriptional regulation of Tnf has been well studied and found to be important for the rapid induction of Tnf mRNA and regulation of the acute phase of inflammation, whereas study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, to that of the constitutive decay element (CDE). We have identified another regulatory element (NRE) in the 3' UTR of Tnf and demonstrate that ARE, CDE, and NRE cooperate in vivo to efficiently downregulate Tnf expression and prevent autoimmune inflammatory diseases. We also show that excessive TNF may lead to embryonic death.