Medeea Badii , Viola Klück , Orsolya Gaal , Georgiana Cabău , Ioana Hotea , Valentin Nica , Andreea M. Mirea , Anca Bojan , Mihnea Zdrenghea , HINT Consortium , Boris Novakovic , Tony R. Merriman , Zhaoli Liu , Yang Li , Cheng-Jian Xu , Cristina Pamfil , Simona Rednic , Radu A. Popp , Tania O. Crişan , Leo A.B. Joosten
{"title":"SOCS3-STAT3 在尿酸盐诱导的人类髓系细胞细胞因子产生过程中的调控作用","authors":"Medeea Badii , Viola Klück , Orsolya Gaal , Georgiana Cabău , Ioana Hotea , Valentin Nica , Andreea M. Mirea , Anca Bojan , Mihnea Zdrenghea , HINT Consortium , Boris Novakovic , Tony R. Merriman , Zhaoli Liu , Yang Li , Cheng-Jian Xu , Cristina Pamfil , Simona Rednic , Radu A. Popp , Tania O. Crişan , Leo A.B. Joosten","doi":"10.1016/j.jbspin.2024.105698","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation.</p></div><div><h3>Methods</h3><p>Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24<!--> <!-->h with varying concentrations of soluble urate, followed by 24<!--> <!-->h restimulation with lipopolysaccharides (LPS)<!--> <!-->±<!--> <!-->monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with <em>JAK2 V617F</em> tyrosine kinase mutation.</p></div><div><h3>Results</h3><p>PBMCs pre-treated with urate produced more interleukin-1beta (IL-1β) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced <em>SOCS3</em> expression in control monocytes but no DNA methylation changes were observed at the <em>SOCS3</em> gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (<em>JAK2 V617F</em> mutation) could not be primed by urate.</p></div><div><h3>Conclusion</h3><p>In vitro, urate exposure increased <em>SOCS3</em> expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.</p></div>","PeriodicalId":54902,"journal":{"name":"Joint Bone Spine","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1297319X24000095/pdfft?md5=bb1140b5d46106c938d331e9e33bb207&pid=1-s2.0-S1297319X24000095-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells\",\"authors\":\"Medeea Badii , Viola Klück , Orsolya Gaal , Georgiana Cabău , Ioana Hotea , Valentin Nica , Andreea M. Mirea , Anca Bojan , Mihnea Zdrenghea , HINT Consortium , Boris Novakovic , Tony R. Merriman , Zhaoli Liu , Yang Li , Cheng-Jian Xu , Cristina Pamfil , Simona Rednic , Radu A. Popp , Tania O. Crişan , Leo A.B. Joosten\",\"doi\":\"10.1016/j.jbspin.2024.105698\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation.</p></div><div><h3>Methods</h3><p>Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24<!--> <!-->h with varying concentrations of soluble urate, followed by 24<!--> <!-->h restimulation with lipopolysaccharides (LPS)<!--> <!-->±<!--> <!-->monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with <em>JAK2 V617F</em> tyrosine kinase mutation.</p></div><div><h3>Results</h3><p>PBMCs pre-treated with urate produced more interleukin-1beta (IL-1β) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced <em>SOCS3</em> expression in control monocytes but no DNA methylation changes were observed at the <em>SOCS3</em> gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (<em>JAK2 V617F</em> mutation) could not be primed by urate.</p></div><div><h3>Conclusion</h3><p>In vitro, urate exposure increased <em>SOCS3</em> expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.</p></div>\",\"PeriodicalId\":54902,\"journal\":{\"name\":\"Joint Bone Spine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1297319X24000095/pdfft?md5=bb1140b5d46106c938d331e9e33bb207&pid=1-s2.0-S1297319X24000095-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Joint Bone Spine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1297319X24000095\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Joint Bone Spine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1297319X24000095","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells
Objective
Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation.
Methods
Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24 h with varying concentrations of soluble urate, followed by 24 h restimulation with lipopolysaccharides (LPS) ± monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation.
Results
PBMCs pre-treated with urate produced more interleukin-1beta (IL-1β) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate.
Conclusion
In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.
期刊介绍:
Bimonthly e-only international journal, Joint Bone Spine publishes in English original research articles and all the latest advances that deal with disorders affecting the joints, bones, and spine and, more generally, the entire field of rheumatology.
All submitted manuscripts to the journal are subjected to rigorous peer review by international experts: under no circumstances does the journal guarantee publication before the editorial board makes its final decision. (Surgical techniques and work focusing specifically on orthopedic surgery are not within the scope of the journal.)Joint Bone Spine is indexed in the main international databases and is accessible worldwide through the ScienceDirect and ClinicalKey platforms.