Activating PP2A Activity Enhances The Anti-inflammatory Function Of ZFP36 In The Inflammatory Response Stimulated By MSU Crystals

Objective:ZFP36 is an RNA-binding protein that can regulate thestability of mRNA of inflammationrelated factors such as IL-1β and COX-2.ZFP36 also has the function of regulating the expression of NLRP3 and the activation of NLRP3 inflammatory bodies.Both the activation of NLRP3 inflammatory bodies and the secretion of IL-1β play a key role in the inflammatory response induced by MSU crystals.At present,there is no report about the role of ZFP36 in gout arthritis.This study is to explore the role of ZFP36 in gout arthritis and its possible mechanism.Methods:The peripheral blood of patients with gout were collected,PBMCs were isolated,and the expression of ZFP36 was detected.After stimulating PBMCs,THP-1 derived macrophages and RAW264.7 cells with different concentrations of monosodium urate(MSU)crystals,the expression of ZFP36 and IL-1β was detected.After suppressing the expression of ZFP36 in THP-1 derived macrophages and RAW264.7 cells,and treating the THP-1 derived macrophages and RAW264.7 cells with PP2A agonist FTY720(promoting the functional activity of ZFP36),respectively,MSU crystals were stimulated to detect ZFP36,IL-1β,TNF-α,IL-6 mRNA levels and NLRP3,Caspase-1,and COX-2 protein expressions.Mice were injected with FTY720 intraperitoneally,and then models of gouty arthritis and peritonitis in mice were constructed to study the effects of FTY720 on their inflammation.Results:The expression levels of ZFP36 and IL-1β in AG group were higher in PBMCs of gout patients than in IG group.After stimulating healthy human PBMCs,THP-1,RAW264.7 cells with MSU crystals,the expression levels of ZFP36 and IL-1β increased significantly.The protein levels of IL-1β,TNF-α,mRNA and NLRP3,mature Caspase-1 and COX-2 in the ZFP36 inhibitory group were higher than those in the control group.After treatment with FTY720,compared with the control,the expression level of ZFP36 increased;while the expression levels of IL-1β,TNF-α mRNA and NLRP3,Caspase-1,COX-2 protein decreased.In the mouse model of gouty arthritis and peritonitis,the degree of swelling of the foot pads and the number of inflammatory cells in the peritoneal lavage fluid of the mice injected with the FTY720 group were significantly reduced.Conclusion:ZFP36 participates in MSU crystal-induced inflammatory response by inhibiting the activation of NLRP3 inflammatory bodies.Enhances the functional activity of ZFP36 and has the function of relieving gouty arthritis.