Monosodium urate crystal-induced pro-interleukin-1β production is post-transcriptionally regulated via the p38 signaling pathway in human monocytes

Abstract

IL-1β is a key mediator of sterile inflammation in response to endogenous particulates, a type of damage-associated molecular pattern (DAMPs) molecule derived from damaged cells. Despite the well-known role of sterile particulates such as monosodium urate (MSU) crystals as inflammasome inducers in monocytes/macrophages, little is known regarding how pro-IL-1β synthesis is induced under sterile inflammatory conditions. We provide evidence that MSU crystals post-transcriptionally induce the rapid production of pro-IL-1β in human primary monocytes. Metabolic labeling and pull-down assays for newly-synthesized proteins clearly showed that MSU crystals rapidly, within 30 min, induce the synthesis of pro-IL-1β as well as global proteins. Notably, MSU crystal-induced pro-IL-1β synthesis is selectively dependent on the p38 MAPK pathway, whereas global protein synthesis is mediated via the mTOR, ERK1/2, and p38 pathways. Furthermore, inhibition of Mnk1, a substrate of p38, blocked MSU crystal-induced pro-IL-1β synthesis downstream of eIF4E phosphorylation. In addition, the p38 MAPK pathway leading to phosphorylation of MK2 was also critical for stabilization of pro-IL-1β mRNA following MSU stimulation. Our findings demonstrate that post-transcriptional regulation via p38 MAPK plays a central role in the rapid synthesis of pro-IL-1β in response to MSU crystals, which is an essential step for IL-1β production in human monocytes.