Intervening the up-regulated SLC7A5 could mitigate the inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes.

Abstract Objective The increased bioenergetic and biosynthetic demands of sustained inflammation and changes to nutrient and oxygen availability are found in rheumatoid arthritis (RA). This study aimed to observe the effects of SLC7A5 (amino acid transporter) on synoviocytes of RA patients and pinpoint the underlying molecular mechanisms. Methods Synovial tissues were collected from OA and RA patients. Fibroblast-like synoviocytes (FLS) were isolated from synovial tissues from RA patients. SLC7A5 expression was evaluated by using RT-qPCR, immunofluorescence and Western blotting. Matrix metalloproteinases (MMPs) expression was evaluated by using RT-qPCR and Western blotting. RNAi and antibody blocking treatments were used to knockdown the expression of SLC7A5 or block its transporting function. Results The SLC7A5 expression was significantly upregulated in the FLS from RA patients compared with that in FLS from OA patients. Cytokine IL-1β played a crucial role in up-regulating SLC7A5 expression via NF-κB pathway in FLS. Intervening SLC7A5 expression with RNAi or blocking SLC7A5 function by monoclonal antibody could ameliorate the MMP3 and MMP13 protein expression. Furthermore, up regulation of SLC7A5 enhanced mTOR-P70SK6 signaling activation which could promote the protein translation of MMP3 and MMP13 in RA FLS. Conclusion SLC7A5 up-regulation could be induced by activated NF-κB pathway, further resulted in an enhanced mTOR-P70S6K activity and the protein expression of MMP3 and MMP13 in FLS from RA patients.

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Intervening up-regulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes.

10.21203/rs.3.rs-19469/v2 ◽

2020 ◽

Author(s):

Jing Xu ◽

Congshan Jiang ◽

Yongsong Cai ◽

Yuanxu Guo ◽

Xipeng Wang ◽

...

Keyword(s):

Amino Acid ◽

Molecular Mechanisms ◽

Inflammatory Mediator ◽

Protein Translation ◽

Activity Assay ◽

Rheumatoid Arthritis Synoviocytes ◽

Synovial Tissues ◽

Mmp13 Expression ◽

Mtor Activity ◽

Fibroblast Like Synoviocytes

Abstract Objective: The disruption of metabolic events and changes to nutrient and oxygen availability due to sustained inflammation in RA increases the demand of bioenergetic and biosynthetic processes within the damaged tissue. The current study aimed to understand the molecular mechanisms of SLC7A5 (amino acid transporter) in synoviocytes of RA patients.Methods: Synovial tissues were obtained from OA and RA patients. Fibroblast-like synoviocytes (FLS) were isolated and SLC7A5 expression was examined by using RT-qPCR, immunofluorescence and Western blotting. RNAi and antibody blocking treatments were used to knockdown SLC7A5 expression or to block its transporter activities. mTOR activity assay and MMPs expression levels were monitored in RA FLS under amino acid deprivation or nutrient rich conditions. Results: RA FLS displayed significantly upregulated expression of SLC7A5 compared to OA FLS. Cytokine IL-1β was found to play a crucial role in up-regulating SLC7A5 expression via NF-κB pathway. Intervening SLC7A5 expression with RNAi or blocking its function by monoclonal antibody ameliorated MMP3 and MMP13 protein expression. Conversely, up regulation of SLC7A5 or tryptophan supplementation enhanced mTOR-P70S6K signals which promoted the protein translation of MMP3 and MMP13 in RA FLS.Conclusion: Activated NF-κB pathway up-regulates SLC7A5, which enhances mTOR-P70S6K activity and MMP3 and MMP13 expression in RA FLS.

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Proteomic analysis of synovial tissue in rheumatoid arthritis, OLFM4 promotes fibroblast like synoviocytes proliferation in RA

10.21203/rs.3.rs-18868/v1 ◽

2020 ◽

Author(s):

Xiaoyu Ren ◽

Ke Xu ◽

Jing Xu ◽

Manman Geng ◽

Chao Lu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Tissue ◽

Western Blotting ◽

Protein Processing ◽

Protein Profiles ◽

Kegg Analysis ◽

Unique Protein ◽

On Line ◽

Synovial Tissues ◽

Fibroblast Like Synoviocytes

Abstract Background To understand the roles of synovial tissue in rheumatoid arthritis (RA), we comprehensively investigated the protein profiles of synovial tissues in patients with RA and osteoarthritis (OA). Methods Protein were isolated from synovial tissues of 46 patients (22 with RA, 24with OA). Proteins were digested and labeled with TMT kit. All the peptide were send to LC-MS/MS analysis, and processed with Mascot and Proteome Discovery (version 1.4) search engines. All the protein data were analysis with Gene ontology (GO) and KEGG on line database. Four up-regulated protein were examined with western blotting and IHC. The RNAi were used for revealing the OLFM4 function in FLS. Results In total, over 500 proteins were identified as the different expression protein compared RA and OA synovia tissues, including 239 proteins were up-regulated in RA, and 271 proteins were up-regulated in OA. GO and KEGG analysis of the different expressed protein mostly identified as developmental processes and protein processing in ER. RT-qPCR, western blotting and IHC confirmed that there was a strong over expressed OLFM4 in RA synovia tissues. OLFM4 could be up-regulated under inflammatory stimulation, and participate in fibroblast like synoviocytes proliferation. Conclusion patients with RA possessed considerably different protein profiles of synovial tissues from with OA. The unique protein profiles of RA synovial tissues, such as the OLFM4 and MZB1 had been up-regulated compared to the OA, may reflect the pathophysiology of RA.

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Identification of drug targets and potential molecular mechanisms for Wantong Jingu Tablet extract in treatment of rheumatoid arthritis: bioinformatics analysis of fibroblast-like synoviocytes

10.21203/rs.3.rs-21336/v2 ◽

2020 ◽

Author(s):

Zhaodong Li ◽

Fangyuan Qi ◽

Fan Li

Keyword(s):

Rheumatoid Arthritis ◽

Western Blotting ◽

Drug Targets ◽

High Performance ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Bioinformatics Analysis ◽

Underlying Mechanism ◽

Dependent Manner ◽

Fibroblast Like Synoviocytes

Abstract Background: Rheumatoid arthritis- fibroblast-like synoviocytes (RA-FLSs) play important roles in pathogenesis of rheumatoid arthritis (RA). Wantong Jingu Tablet (WJT), a mixture of traditional Chinese medicine, is a potentially effective therapy for RA, but its underlying mechanism is unclear. In this study, we explore the effects of WJT on human RA-FLSs and the underlying molecular mechanism. Methods: The major components of WJT were determined using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Cell proliferative ability was evaluated by CCK-8, colony formation assay, and EdU incorporation assay. Cell apoptotic capacity was examined by caspase-3 and caspase-9 activity test. Protein levels of Bax and Bcl-2 were investigated by western blotting. High-throughput sequencing and bioinformatics analysis were conducted to screen and identify targeted genes, followed by identification by qRT-PCR and western blotting. Results: In this study, we have identified 346 compounds in WJT. Our results showed that WJT inhibited the RA-FLSs proliferation, and promoted apoptosis in a dose- and time-dependent manner. More importantly, 184 differentially expressed genes (DEGs) has been screened after WJT treatment based on DEGSeq2 and 278 DEGs was identified by DEGSeq2 combined with WGCNA. Then, 10 hub genes were identified based on two different analyses, while the expression levels of only SMC3, THOC1, BUB1, and STAG2 were decreased after WJT treatment, which was identical to the sequencing profiles.Conclusions: WJT exerted its anti-proliferation and pro-apoptosis effects possibly through suppressing the expression of SMC3, THOC1, BUB1, and STAG2 in RA-FLSs. Thus, therapeutics targeting these genes may be a promising strategy for rescuing RA.

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Identification of drug targets and potential molecular mechanisms for Wantong Jingu Tablet extract in treatment of rheumatoid arthritis: bioinformatics analysis of fibroblast-like synoviocytes

10.21203/rs.3.rs-21336/v1 ◽

2020 ◽

Author(s):

Zhaodong Li ◽

Fangyuan Qi ◽

Fan Li

Keyword(s):

Rheumatoid Arthritis ◽

Western Blotting ◽

Drug Targets ◽

High Performance ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Bioinformatics Analysis ◽

Underlying Mechanism ◽

Dependent Manner ◽

Fibroblast Like Synoviocytes

Abstract Background: Rheumatoid arthritis- fibroblast-like synoviocytes (RA-FLSs) play important roles in pathogenesis of rheumatoid arthritis (RA). Wantong Jingu Tablet (WJT), a mixture of traditional Chinese medicine, is a potentially effective therapy for RA, but its underlying mechanism is unclear. In this study, we explore the effects of WJT on human RA-FLSs and the underlying molecular mechanism. Methods: The major components of WJT were determined using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Cell proliferative ability was evaluated by CCK-8, colony formation assay, and EdU incorporation assay. Cell apoptotic capacity was examined by caspase-3 and caspase-9 activity test. Protein levels of Bax and Bcl-2 were investigated by western blotting. High-throughput sequencing and bioinformatics analysis were conducted to screen and identify targeted genes, followed by identification by qRT-PCR and western blotting. Results: In this study, we have identified 346 compounds in WJT. Our results showed that WJT inhibited the RA-FLSs proliferation, and promoted apoptosis in a dose- and time-dependent manner. More importantly, 184 differentially expressed genes (DEGs) has been screened after WJT treatment based on DEGSeq2 and 278 DEGs was identified by DEGSeq2 combined with WGCNA. Then, 10 hub genes were identified based on two different analyses, while the expression levels of only SMC3 , THOC1 , BUB1 , and STAG2 were decreased after WJT treatment, which was identical to the sequencing profiles.Conclusions: WJT exerted its anti-proliferation and pro-apoptosis effects possibly through suppressing the expression of SMC3, THOC1, BUB1, and STAG2 in RA-FLSs. Thus, therapeutics targeting these genes may be a promising strategy for rescuing RA. Keywords: Rheumatoid arthritis; bioinformatics; fibroblast-like synoviocytes; Wantong Jingu Tablet

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MiRNA-6089 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting CCR4

10.21203/rs.3.rs-20663/v1 ◽

2020 ◽

Author(s):

Suxian Lin ◽

Zhiyong Zhang ◽

Shengnan Wang ◽

Yang Lu ◽

Meilv Yang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Protein Expression ◽

Caspase 3 ◽

Healthy Controls ◽

Quantitative Real Time Pcr ◽

Qrt Pcr ◽

Tnf Α ◽

Proliferation And Apoptosis ◽

Synovial Tissues ◽

Fibroblast Like Synoviocytes

Abstract Background: Growing data have indicated that fibroblast-like synoviocytes (FLS) and miRNAs are implicated in the pathogenesis of rheumatoid arthritis (RA). This study was aimed to evaluate the function of miR-6089 in the regulation of RA-FLSs. Methods: The expression of miR-6089 was measured by quantitative real time PCR (qRT-PCR). The RA-FLSs were transfected with si-CCR4 plasmids or miR-6089 mimic, and subjected to CCK-8 and flow cytometry to analyze proliferation and apoptosis. The concentrations of MMP-1, TNF-α and IL-6 in RA-FLSs supernatant were detected using ELISA. The protein expression of caspase-3, -8 and -9 was detected using western blot.Results: The levels of miR-6089 were detected to be significantly lower in the synovial tissues and FLSs of RA than in the synovial tissues and FLSs of healthy controls. The miR-6089 up-regulation in RA-FLSs significantly inhibited the proliferation and promoted cell apoptosis accompany with an increase protein expression of caspase-3, -8 and -9. Furthermore, CCR4 was determined to directly target miR-6089, and its expression was significantly increased in the synovial tissues of RA than in the synovial tissues of healthy controls. Moreover, CCR4 overexpression effectively reversed the effect on proliferation and apoptosis induced by miR-6089 in RA-FLSs. Conclusion: Our results revealed that miR-6089 may be a potential target for RA prevention and therapy of RA.

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Knockdown of nrf2 Exacerbates TNF-α-Induced Proliferation and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes through Activating JNK Pathway

Journal of Immunology Research ◽

10.1155/2020/6670464 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Yu Du ◽

Qian Wang ◽

Na Tian ◽

Meng Lu ◽

Xian-Long Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Western Blotting ◽

Nuclear Translocation ◽

Cell Counting ◽

Related Factor ◽

Jnk Pathway ◽

Tnf Α ◽

Synovial Tissues ◽

Proliferation And Invasion ◽

Fibroblast Like Synoviocytes

Fibroblast-like synoviocytes (FLS) in the synovial tissue of rheumatoid arthritis (RA) exhibit over-proliferative and aggressive phenotypes, which participate in the pathophysiology of RA. In RA, little is known about the nonantioxidant effect of nuclear factor erythroid 2-related factor 2 (nrf2), the master regulator of redox homeostasis. In this study, we aimed to explore the expression and upstream regulatory factors of nrf2 and revealed its functions in modulating the proliferation and invasion in RA-FLS. FLS were isolated from RA and osteoarthritis patients. Expression of nrf2 in the synovial tissues and FLS was analyzed by immunohistochemistry, real-time PCR, Western blotting, and immunofluorescence staining. Cell proliferation was examined by Cell Counting Kit-8. Cell invasion was tested by transwell assay. Phosphorylation of JNK was determined by Western blotting. The results showed that nrf2 expression in the RA synovial tissues was upregulated. TNF-α promoted expression and nuclear translocation of nrf2 in RA-FLS and increased the intracellular reactive oxygen species (ROS) level. Nrf2 nuclear translocation was blocked by ROS inhibitor N-acetylcysteine. Both knockdown of nrf2 by siRNA and inhibition of nrf2 by ML385 significantly promoted the TNF-α-induced proliferation and invasion of RA-FLS. Activation of nrf2 by sulforaphane (SFN) profoundly inhibited the TNF-α-induced proliferation and invasion of RA-FLS. Knockdown of nrf2 also enhanced the TNF-α-induced matrix metalloproteinases (MMPs) expression and phosphorylation of JNK in RA-FLS. Proliferation and invasion of RA-FLS incubated with TNF-α and nrf2 siRNA were inhibited by pretreatment with JNK inhibitor SP600125. In conclusion, nrf2 is overexpressed in synovial tissues of RA patients, which may be promoted by TNF-α and ROS levels. Activation of nrf2 may suppress TNF-α-induced proliferation, invasion, and MMPs expression in RA-FLS by inhibiting JNK activation, indicating that nrf2 plays a protective role in relieving the severity of synovitis in RA. Our results might provide novel insights into the treatment of RA.

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Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

Biomolecules ◽

10.3390/biom9120795 ◽

2019 ◽

Vol 9 (12) ◽

pp. 795 ◽

Cited By ~ 12

Author(s):

Qing Zhang ◽

Jia Liu ◽

Mengmeng Zhang ◽

Shujun Wei ◽

Ruolan Li ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Mechanisms ◽

Herbal Medicines ◽

Janus Kinase ◽

Mitogen Activated Protein Kinase ◽

Signal Pathways ◽

Apoptosis Induction ◽

Apoptotic Pathway ◽

Induction Of Apoptosis ◽

Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a known chronic autoimmune disease can cause joint deformity and even loss of joint function. Fibroblast-like synoviocytes (FLS), one of the main cell types in synovial tissues of RA patients, are key effector cells in the development of RA and are considered as promising therapeutic targets for treating RA. Herbal medicines are precious resources for finding novel agents for treating various diseases including RA. It is reported that induction of apoptosis in FLS is an important mechanism for the herbal medicines to treat RA. Consequently, this paper reviewed the current available references on pro-apoptotic effects of herbal medicines on FLS and summarized the related possible signal pathways. Taken together, the main related signal pathways are concluded as death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other reported pathways such as janus kinase/signal transducers and activators of transcription (JAK-STAT) signal pathway. Understanding the apoptosis induction pathways in FLS of these herbal medicines will not only help clear molecular mechanisms of herbal medicines for treating RA but also be beneficial for finding novel candidate therapeutic drugs from natural herbal medicines. Thus, we expect the present review will highlight the importance of herbal medicines and its components for treating RA via induction of apoptosis in FLS, and provide some directions for the future development of these mentioned herbal medicines as anti-RA drugs in clinical.

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Loss of imprinting of IGF2 characterises high IGF2 mRNA-expressing type of fibroblast-like synoviocytes in rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.106195 ◽

2009 ◽

Vol 69 (6) ◽

pp. 1239-1242 ◽

Cited By ~ 6

Author(s):

Alejandro Martin-Trujillo ◽

Johanna G I van Rietschoten ◽

Trieneke C G Timmer ◽

Francisco Milena Rodríguez ◽

Tom W J Huizinga ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Thymidine Incorporation ◽

Biallelic Expression ◽

Transcript Quantification ◽

Loss Of Imprinting ◽

Relative Contribution ◽

Quantification Analysis ◽

Allele Specific ◽

Synovial Tissues ◽

Fibroblast Like Synoviocytes

ObjectiveIncreased expression of insulin-like growth factor 2 (IGF2) by fibroblast-like synoviocytes (FLS) was associated with low inflammatory synovium of patients with rheumatoid arthritis (RA). The aim of this study was to analyse whether the differential expression of IGF2, whose expression is normally restricted to one allele, is due to activation of the normally suppressed allele.MethodsIGF2 gene expression of RA FLS was quantified by quantitative real-time PCR. FLS heterozygous for a 3′-untranslated region IGF2 polymorphism were selected to measure the relative contribution of the allelic transcripts by allele-specific transcript quantification assay. Proliferation was determined by [3H]thymidine incorporation.ResultsIGF2 was shown to contribute to RA FLS proliferation. FLS could be classified in IGF2 high and IGF2 low-expressing cell lines. Allelic IGF2 transcript quantification analysis revealed that in part of the RA FLS the normally suppressed allele was activated, resulting in biallelic expression of the IGF2 gene. Biallelic expression was associated with increased levels of IGF2 mRNA production.ConclusionThe findings indicate that the imprinting status of IGF2 might underlie the increased expression of IGF2, which may contribute to autonomous growth of RA FLS of low inflammatory synovial tissues.

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MiR-498 suppresses proliferation and inflammation in fibroblast-like synoviocytes in rheumatoid arthritis via targeting JAK1

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v18i10.2 ◽

2021 ◽

Vol 18 (10) ◽

pp. 2011-2017

Author(s):

Lan Chai ◽

Xian Zhen Zhang ◽

Hai fang Ma ◽

Fang Yuan

Keyword(s):

Rheumatoid Arthritis ◽

Cell Cycle ◽

Polymerase Chain Reaction ◽

Therapeutic Target ◽

Cell Apoptosis ◽

Inflammatory Responses ◽

Chain Reaction ◽

Polymerase Chain ◽

Synovial Tissues ◽

Fibroblast Like Synoviocytes

Purpose: To investigate the effect of microRNA 498 (miR-498) on proliferation and inflammation of rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs) in rheumatoid arthritis (RA). Methods: MiR-498 level was evaluated in both RA synovial tissues and RA-FLSs using real-time polymerase chain reaction (PCR). MicroRNA-498 overexpression or knockdown was performed in RAFLSs. Proliferation, apoptosis, cell cycle and inflammation induced by miR-498 mimics or inhibitor were used to explore the function of miR-498 in RA. Results: Expression level of miR-498 was downregulated in both RA synovial tissues and RA- FLSs. MicroRNA-498 mimics decreased proliferation and arrested cell cycle, whereas miR-498 inhibitor caused the opposite effects in RA-FLSs. In addition, miR-498 mimics suppressed inflammation and promoted cell apoptosis, while miR-498 inhibitor promoted inflammation and inhibited cell apoptosis in RA-FLSs. Furthermore, the effect of miR-498 on the proliferation, inflammation and apoptosis of RAFLSs was mediated by its ability to target and downregulate JAK1. Conclusion: These results indicate that miR-498 inhibits the proliferation and inflammatory responses of RA-FLSs by targeting JAK1, thus revealing a new therapeutic target for RA treatment.

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Uridine Diphosphate (UDP) Promotes Rheumatoid Arthritis Through P2Y6 Activation

10.21203/rs.3.rs-56879/v2 ◽

2020 ◽

Author(s):

Hongxing Wang ◽

Hui Wu ◽

Kehua Fang ◽

Xiaotian Chang

Keyword(s):

Rheumatoid Arthritis ◽

Cell Proliferation ◽

Real Time ◽

Proinflammatory Cytokines ◽

Uridine Diphosphate ◽

Synovial Fluids ◽

Synovial Tissues ◽

And Migration ◽

G Protein Coupled ◽

Fibroblast Like Synoviocytes

Abstract Background: Uridine diphosphate (UDP) is an extracellular nucleotide signaling molecule implicated in diverse biological processes via specific activation of pyrimidinergic receptor P2Y, G Protein-Coupled, 6 (P2Y6). There is very little knowledge about the function and mechanism of UDP in rheumatoid arthritis (RA).Methods: This study used a quasi-targeted liquid chromatography-mass spectrometry (LC-MS) approach to investigate the unique expression of metabolites in RA synovial fluids (SF) (n = 10) with samples from osteoarthritis (OA) as controls (n = 10). RA fibroblast-like synoviocytes (FLSs) were collected from synovial tissues (n = 5) and cultured with UDP or MRS2578, a P2Y6 antagonist, and FLSs from OA were used as controls (n = 5). Rats with collagen-induced arthritis (CIA) were injected with UDP, MRS2578 or both (n = 9 for each group). P2Y6 expression was examined using real-time PCR, Western blotting and immunohistochemistry. Cell proliferation, apoptosis and migration of RA FLSs were measured using CCK-8 assay, real-time cell analysis, flow cytometry, wound healing assay and Transwell assay, respectively. The UDP levels in the culture medium, synovial fluid (n = 36) and peripheral blood (n = 36) of RA and CIA rats were measured using a Transcreener UDP Assay. Levels of proinflammatory cytokines were measured using a flow assay. Interleukin-6 (IL-6) levels were measured using ELISA and flowResults：LC-MS analysis detected significantly increased UDP levels in RA SF compared with OA SF, and the level was positively correlated with anticyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) levels in RA. The increased UDP concentration was verified in the blood and synovial fluids of RA patients compared with samples from OA patients and healthy volunteers, respectively. UDP stimulated cell proliferation, migration and IL-6 secretion in RA FLSs and inhibited their apoptosis in culture, and MRS2578 inhibited these effects of UDP. UDP injection accelerated CIA and stimulated IL-6 production rather than other proinflammatory cytokines in the rat model, but simultaneous injection of MRS2578 suppressed these effects and alleviated CIA. P2Y6 expression was increased in RA and CIA synovial tissues.Conclusion: These results suggest that UDP is highly expressed in RA and stimulates RA pathogenesis by promoting P2Y6 activities to increase IL-6 production.

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