Abstract
BackgroundInterleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout. However, the underlying mechanism through which the production of IL-1β is regulated has not been fully elucidated. Our previous work identified that miR-302b had an important immune regulatory role in bacterial lung infections. This study was conducted to evaluate the function of miR-302b on monosodium urate (MSU) crystal-induced inflammation and its mechanism.MethodsThe expression pattern and the immune-regulatory role of miR-302b were evaluated both in vitro and in vivo. The functional targets of miR-302b were predicted by bioinformatics, and then validated by genetic approaches. In addition, the clinical feature of miR-302b was analyzed using serum samples of patients with gouty arthritis.ResultsThe extremely high expression of miR-302b was observed in both macrophages and mouse air membranes treated with MSU. Intriguingly, overexpression of miR-302b regulated NF-κB and caspase-1 signaling, leading to significantly attenuate MSU-induced IL-1β. By genetic analysis, miR-302b exhibited inhibitory function on IRAK4 and EphA2 by binding to their 3′-UTR regions. Corporately silencing IRAK4 and EphA2 largely impaired MSU-induced IL-1β protein production. Moreover, it was also found that miR-302b and EphA2 suppressed the migration of macrophages. Finally, it was observed that high expression of miR-302b was a general feature in patients with gouty arthritis.ConclusionsThese results suggest that miR-302b can regulate IL-1β production in MSU-induced inflammation by targeting NF-κB and caspase-1 signaling, and may be a potential therapeutic target for gouty arthritis.
Highlights
Interleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout
We further determined that interleukin-1 receptor-associated kinase 4 (IRAK4) and Eph receptor A2 (EphA2) expression was enhanced upon monosodium urate (MSU) treatment, found in MSU-stimulated THP-1 cells (Fig. 4b, c), and these results indicated that IRAK4 and EphA2 may function in MSU-induced inflammation
We subsequently evaluated whether IRAK4 and EphA2 were the functional targets of miR-302b by siRNAmediated IRAK4 and EphA2 knockdown in the THP-1 cells (Fig. 4e, h), and ELISA results showed that the IL-1β protein expression level was repressed in the supernatant of THP-1 cells transfected with IRAK4 or EphA2 siRNA compared to the controls (Fig. 4f, i)
Summary
Interleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout. The underlying mechanism through which the production of IL-1β is regulated has not been fully elucidated. This study was conducted to evaluate the function of miR-302b on monosodium urate (MSU) crystal-induced inflammation and its mechanism. Gout is a metabolic disease that is usually characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in the joints and subsequent induction of acute inflammatory response and cartilage destruction [1]. IL-1β is a major effector cytokine and plays a crucial role in the MSU-induced initiation of acute gout flares [1]. Purified MSU crystals could not solely induce IL-1β production or joint inflammation [4].
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