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.
Highlights
Proteolytic cleavage by caspase 1 for maturation
We demonstrate that monosodium urate (MSU) crystals induce rapid pro-IL-1βsynthesis in a translation-dependent manner through the p38/MAPK-interacting protein kinases 1 (Mnk1)/eIF4E pathway, and that this is an essential step for IL-1βproduction in primary human monocytes
Since the effect of sterile particulates such as MSU on IL-1βproduction has largely been investigated using THP-1 cells pre-stimulated with Phorbol 12-Myristate 13-Acetate (PMA), the priming stimuli for pro-IL-1βproduction has yet to be identified[30]
Summary
Proteolytic cleavage by caspase 1 for maturation. The activation of caspase 1 occurs following the assembly of an inflammasome complex during the activation step and leads to cleavage of pro-IL-1βto mature IL-1β, which is released into the extracellular environment[12]. Among a variety of DAMPs, sterile particulates including monosodium urate (MSU) and cholesterol crystals are capable of inducing robust inflammatory responses This excessive and unremitting inflammation causes damage to healthy tissue and underlies the pathogenesis of many crystal-based diseases[13,14]. The inflammasome is an essential signaling complex for active IL-1βproduction[17,18,19], and IL-1β-driven inflammation might contribute to the development of other comorbidities including hypertension, diabetes mellitus and cardiovascular disease in patients with gout[8,20] Both the priming and activation steps are prerequisite for productive IL-1βgeneration[21], much attention has been paid to understanding how endocytosed sterile particulates initiate the activation of the NLRP3 inflammasome resulting in the production of mature IL-1βin monocytes/macrophages. We hypothesized that sterile particulates, including MSU, might be involved in the production of pro-IL-1βduring the priming step, which is critical for the production of active IL-1βby human monocytes
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