beta-Arrestins (beta-arrestin-1 and -2) are multifunctional proteins that play important roles in the regulation of inflammation and cell survival that need to be tightly controlled; however, the mechanism that underlies their gene expression is largely unclear. Here, we demonstrate that -arrestin-1 is a transcriptional target of NF-B. mRNA and protein levels of -arrestin-1 were up-regulated by NF-B inducers. Inhibition of NF-B prevented the up-regulation of -arrestin-1 mRNA, whereas activation of NF-B led to increased -arrestin-1 expression. -Arrestin-1 promoter activity was consistently enhanced upon NF-B activation as a result of the presence of a highly conserved B site. -Arrestin-1, in turn, suppressed the transcriptional activity of NF-B by interfering with the interaction between p65 and p50. -Arrestin-1-deficient mice displayed reduced TNF--induced cell death and increased expression of antiapoptotic genes. Reintroduction of -arrestin-1, but not its mutant, which is unable to interfere with the p65-p50 interaction, into -arrestin-deficient mouse embryonic fibroblasts partially restored sensitivity to TNF--induced cell death. These findings reveal NF-B and -arrestin-1 to be key components of a negative feedback circuit that is necessary to regulate cell death.Li, J., Guo, A., Wang, Q., Li, Y., Zhao, J., Lu, J., Pei, G. NF-B directly regulates beta-arrestin-1 expression and forms a negative feedback circuit in TNF-alpha-induced cell death.