p38α stabilizes interleukin-6 mRNA via multiple AU-rich elements

AU-rich elements (AREs) in the 3′-untranslated region (UTR) of unstable mRNA dictate their degradation or mediate translational repression. Cell signaling through p38α MAPK is necessary for post-transcriptional regulation of many pro-inflammatory cytokines. Here, the cis-acting elements of interleukin-6 (IL-6) 3′-UTR mRNA that required p38α signaling for mRNA stability and translation were identified. Using mouse embryonic fibroblasts (MEFs) derived from p38α^+/+ and p38α^-/- mice, we observed that p38α is obligatory for the IL-1-induced IL-6 biosynthesis. IL-6 mRNA stability is promoted by p38α via 3′-UTR. To understand the mechanism of cis-elements regulated by p38α at post-transcriptional level, truncation of 3′-UTR and the full-length 3′-UTR with individual AUUUA motif mutation placed in gene reporter system was employed. Mutation-based screen performed in p38α^+/+ and p38α^-/- mouse embryonic fibroblast cells revealed that ARE1, ARE2, and ARE5 in IL-6 3′-UTR were targeted by p38α, and truncation-based screen showed that IL-6 3′-UTR-(56-173) was targeted by p38α to stable mRNA. RNA secondary structure analysis indicated that modulated reporter gene expression was consistent with predicted secondary structure changes.