Posttranscriptional regulatory elements in the 3'-untranslated region (UTR) of mRNAs play an important role in mRNA stabilization. Induction of I kappa B-zeta, a critical transcriptional regulator in the innate immune response, is mediated via specific mRNA stabilization by lipopolysaccharide (LPS) and interleukin (IL)-1 beta It is known that the 3'-UTR of I kappa B-zeta, especially 165 nucleotides after the stop codon, plays a crucial role in mRNA stability. Herein, we show that AU-rich elements and miRNA targets in these 165 3'-UTR nucleotides are dispensable for stability of mRNA. Additionally, NF-kappa B activation is important for I kappa B-zeta transcription, but dispensable for I kappa B-zeta mRNA stability. Interestingly, high-throughput screening results show that MyD88, a signal molecule responsive to LPS/IL-1 beta stimulation, is key for stabilizing I kappa B-zeta mRNA expression. Moreover, MyD88-deficient macrophages exhibited a decreased half-life of I kappa B-zeta mRNA expression. These results indicate that the LPS/IL-1 beta-MyD88 axis plays a crucial role for stabilization of I kappa B-zeta mRNA. (C) 2015 The Authors. Published by Elsevier Inc.