The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilizationvia MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism

Stabilization of mRNAs contributes to the strong and rapid induction of gen es in the inflammatory response. The signaling mechanisms involved were inv estigated using a tetracycline-controlled expression system to determine th e half-lives of interleukin (IL)-6 and IL-8 mRNAs, Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitut ively active form of the MAP kinase kinase kinase MEKK1. Destabilization an d signal-induced stabilization was transferred to the stable beta-globin mR NA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich regi on, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF m RNAs, Of the different MEKK1-activated signaling pathways, no significant e ffects on mRNA degradation were observed for the SAPK/JNK, extracellular re gulated kinase and NF-KB pathways. Selective activation of the p38 MAP kina se (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A do minant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL- l-induced stabilization. Furthermore, an active form of the p38 MAP kinase- activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whe reas a negative interfering MK2 mutant interfered with MAP kinase kinase 6- induced stabilization. These findings indicate that the p38 MAP kinase path way contributes to cytokine/stress-induced gene expression by stabilizing m RNAs through an MK2-dependent, ARE-targeted mechanism.