G protein coupled receptors(GPCRs)are transmembrane receptor proteins,which allow signals to transfer across membrane.GPCRs include a large number of receptors,different receptors mediated different signaling pathways...G protein coupled receptors(GPCRs)are transmembrane receptor proteins,which allow signals to transfer across membrane.GPCRs include a large number of receptors,different receptors mediated different signaling pathways of GPCRs-adenylyl cyclase(AC)-cyclic adenosine 3',5'-monophosphate(c AMP),including β2 adrenergic receptors(β2-ARs)-AC-c AMP signaling pathways,E-prostanoid2/4(EP2/4)-AC-cA MP signaling pathways.Regulatory proteins,such as G protein coupled receptor kinases(GRKs)andβ-arrestins,play important modulatory roles in GPCRs signaling pathway.GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.Rheumatoid arthritis(RA)is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response.This article review the advances on GPCRs signaling pathway implicating in the inflammatory and immune response of RA.展开更多
Rheumatoid arthritis(RA)is a systemic,inflammatory autoimmune disease,which is still a significant unmet medical need despite significant therapeutic advances.The pathogenesis of RA involves many types of immune cells...Rheumatoid arthritis(RA)is a systemic,inflammatory autoimmune disease,which is still a significant unmet medical need despite significant therapeutic advances.The pathogenesis of RA involves many types of immune cells,such as T cells,B cells,macrophages and so on.It′s known that the synovial membrane contains two layers,the outer layer,or subintima and the inner layer,or intima.The intimal cells mainly include two types of cells,fibroblasts synoviocyte and macrophage-like synoviocyte.In the inflamed rheumatoid synovial tissues,there is a large number of macrophage-like synoviocytes.These cells can produce key pro-inflammatory cytokines,chemokines and growth factors and their signaling pathways,including nuclear factorκB,Janus kinase-signal transducer,are highly activated.It will trigger cartilage destruction and perpetuate inflammation.This review attempts to high-light some aberrations of macrophage in immunoreaction including the roles of genetic and environmental factors,cellular alterations,especially signaling pathways that are implicated in the pathogenesis of RA.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their ...Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their diminution.However,the origin of these sublining macrophages in synovium(including infiltrated macrophages and tissue-resident macrophages)are still unknown both in animal models of arthritis and RA patients,let alone the differences and feature of these macrophages.In rheumatic synovium,macrophages are submitted to a large variety of micro-environmental signals which influence the phenotypic polarization and activation of macrophages.Understanding the mechanisms and functional consequences of the heterogeneous macrophages will contribute to confirm their potential role in synovial inflammation development.Furthermore,research on macrophage plasticity to soft-control their phenotypic polarization could lead to novel therapeutic approaches.展开更多
OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injure...OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.展开更多
OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associat...OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associated with clinical variables and lab parameters.METHODS Blood samples and peripheral blood mononuclear cells from RA patients and healthy controls(HCs)were collected and isolated respectively.Clinical variables and lab parameters,BAFF level,cytokines and immunoglobulins in serum were evaluated at entry.B cell subpopulations,BAFF receptors(BAFFR,BCMA,TACI),and alternative and canonical NF-κB pathway in B cell were analyzed in vivo and in vitro.RESULTS In RA patients,BAFF level and activated B cell subsets increased significantly.BAFF level was associated with CRP,RF,DAS28,swollen joint counts and tender joint counts.BAFFR,BCMA,TACI on B cells in RA over expressed.The expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52 were higher than that in HCs.In vitro,BAFF up regulated activated B cell subset and the expressions of BAFFR,BCMA and TACI.BAFF also enhanced the expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52.CONCLUSION Increased BAFF in serum is associated with the disease activity of RA,BAFF involves in the proliferation and activation of B cell in RA through alternative and canonical NF-κB pathway,indicating that BAFF might be a novel biomarker of diagnosis and therapy.展开更多
OBJECTIVE Aryl hydrocarbon receptor(Ahr)is thought to be a crucial factor that regulates immune responses,which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis(RA).The res...OBJECTIVE Aryl hydrocarbon receptor(Ahr)is thought to be a crucial factor that regulates immune responses,which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis(RA).The results of our group in recent years have shown that CP-25,a novel ester derivative of paeoniflorin,has a good effect on improving RA animal models.However,whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear.METHODS CP-25 treatment ameliorated adjuvant-induced arthritis(AA),a mouse model of RA,by inhibiting Ahr-related activities in fibroblasts like synoviocytes(FLS).AA rats were treated with CP-25 or paroxetine from day 17 to 33 after immunization.RESULTS CP-25 alleviated arthritis symptoms and the pathological changes,decreased the expression of Ahr in the synovium and FLS of AA rats.Besides,treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation.In addition,we also demonstrated that CP-25 down-regulated the co-expression and co-localization of Ahr and G protein-coupled receptor kinase 2(GRK2)in MH7A.CONCLUSION The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA,which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.展开更多
基金supported by National Natural Science Foundation of China(81330081,81473223and 81673444)Anhui Province Postdoctoral Science Foundation(2016B134)
文摘G protein coupled receptors(GPCRs)are transmembrane receptor proteins,which allow signals to transfer across membrane.GPCRs include a large number of receptors,different receptors mediated different signaling pathways of GPCRs-adenylyl cyclase(AC)-cyclic adenosine 3',5'-monophosphate(c AMP),including β2 adrenergic receptors(β2-ARs)-AC-c AMP signaling pathways,E-prostanoid2/4(EP2/4)-AC-cA MP signaling pathways.Regulatory proteins,such as G protein coupled receptor kinases(GRKs)andβ-arrestins,play important modulatory roles in GPCRs signaling pathway.GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.Rheumatoid arthritis(RA)is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response.This article review the advances on GPCRs signaling pathway implicating in the inflammatory and immune response of RA.
基金supported by National Natural Science Foundation of China(81330081,81473223 and 81673444)
文摘Rheumatoid arthritis(RA)is a systemic,inflammatory autoimmune disease,which is still a significant unmet medical need despite significant therapeutic advances.The pathogenesis of RA involves many types of immune cells,such as T cells,B cells,macrophages and so on.It′s known that the synovial membrane contains two layers,the outer layer,or subintima and the inner layer,or intima.The intimal cells mainly include two types of cells,fibroblasts synoviocyte and macrophage-like synoviocyte.In the inflamed rheumatoid synovial tissues,there is a large number of macrophage-like synoviocytes.These cells can produce key pro-inflammatory cytokines,chemokines and growth factors and their signaling pathways,including nuclear factorκB,Janus kinase-signal transducer,are highly activated.It will trigger cartilage destruction and perpetuate inflammation.This review attempts to high-light some aberrations of macrophage in immunoreaction including the roles of genetic and environmental factors,cellular alterations,especially signaling pathways that are implicated in the pathogenesis of RA.
基金supported by National Natural Science Foundation of China(31200675,81573443,81330081 and 81673444)Specialized Research Fund for the Doctoral Program of Higher Education(20123420110003)Scientific Research of BSKY from Anhui Medical University(XJ201215)
文摘Rheumatoid arthritis(RA)is an autoimmune disease,which is characterized by synovial inflammation.Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their diminution.However,the origin of these sublining macrophages in synovium(including infiltrated macrophages and tissue-resident macrophages)are still unknown both in animal models of arthritis and RA patients,let alone the differences and feature of these macrophages.In rheumatic synovium,macrophages are submitted to a large variety of micro-environmental signals which influence the phenotypic polarization and activation of macrophages.Understanding the mechanisms and functional consequences of the heterogeneous macrophages will contribute to confirm their potential role in synovial inflammation development.Furthermore,research on macrophage plasticity to soft-control their phenotypic polarization could lead to novel therapeutic approaches.
基金National Natural Science Foundation of China(8187303981973547)Natural Science Foundation of Shandong Province(ZR2017MH068)
文摘OBJECTIVE To investigate the anti-rheumatoid arthritis(RA)effect of Escin combined with low dose of GCs(dexameth⁃asone,Dex)and its underlying mechanism.METHODS Adjuvant-induced rheumatoid arthritis rats and LPS-injured RAW 264.7 were used to investigate the anti-RA effects of Escin combined with low dose Dex in vivo and in vitro.In vivo experiment:rats were randomly divided into model group(AIA),dexamethasone high dose(Dex,0.2 mg·kg^-1)group,dexamethasone low dose(Dex,0.05 mg·kg^-1)group,Escin 10 mg·kg^-1 group,Dex 0.05+Escin group,10 rats in each group,another 10 were used as normal control group.The vehicle and the corresponding drug were administered intragastrically(ig)daily for 14 d.In vitro experiment:LPS was used to stimulate RAW 264.7 macrophages for inflammatory models,which were divided into control group,LPS group,Dex with high dose(50 nmol·L^-1)group,and Dex with low dose(12.5 nmol·L^-1)group.In the Escin 10μmol·L^-1 group and the Dex+Escin(12.5 nmol·L^-1+10μmol·L^-1)group,the corresponding drugs were added to each well.After 2 h,LPS was added to induce inflammation.RESULTS Escin combined with low dose Dex significantly decreased arthritic index,serum IL-6 and TNF-α,improved paw swelling,and ameliorated the joint pathology immune organ pathology significantly.Gene chip results revealed that Nr3c1(GR)altered significantly.And that GR activation by Escin and low dose Dex was confirmed both in vivo and in vitro.Furthermore,Escin combined with low dose Dex also significant increase GR mRNA expression.However,when suppression of GR by its specific inhibitor,the anti-RA effect of Escin combined with low dose Dex was abolished.CONCLUSION Escin combined with Dex reduces the dose of Dex,and exerts significant anti-RA effects,which could also reduce the adverse effects of Dex.This combination might be attributed to GR activation.This study might provide a new combination drugs for the treatment of RA.
基金The project supported by National Natural Science Foundation of China(81473223,31100640,81302517 and 81330081)China Postdoctoral Science Foundation(2013M540509)
文摘OBJECTIVE To investigate the contribution of B cell activating factor of TNF family(BAFF)in the proliferation and activation of B cell in rheumatoid arthritis(RA),and to clarify whether high levels of BAFF is associated with clinical variables and lab parameters.METHODS Blood samples and peripheral blood mononuclear cells from RA patients and healthy controls(HCs)were collected and isolated respectively.Clinical variables and lab parameters,BAFF level,cytokines and immunoglobulins in serum were evaluated at entry.B cell subpopulations,BAFF receptors(BAFFR,BCMA,TACI),and alternative and canonical NF-κB pathway in B cell were analyzed in vivo and in vitro.RESULTS In RA patients,BAFF level and activated B cell subsets increased significantly.BAFF level was associated with CRP,RF,DAS28,swollen joint counts and tender joint counts.BAFFR,BCMA,TACI on B cells in RA over expressed.The expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52 were higher than that in HCs.In vitro,BAFF up regulated activated B cell subset and the expressions of BAFFR,BCMA and TACI.BAFF also enhanced the expressions of MKK3,MKK6,p-p38,p-NF-κB65,TRAF2,NF-κB52.CONCLUSION Increased BAFF in serum is associated with the disease activity of RA,BAFF involves in the proliferation and activation of B cell in RA through alternative and canonical NF-κB pathway,indicating that BAFF might be a novel biomarker of diagnosis and therapy.
基金National Nature Science Foundation of China(81573443,82173824,81973332)Anhui Province Natural Science Fund(170808J10)+1 种基金Anhui Provincial Natural Science Foundation(2108085MH320)and Collaborative Innovation Project of Key Scientific Research Platform in Anhui Universities(GXXT-2020-065)。
文摘OBJECTIVE Aryl hydrocarbon receptor(Ahr)is thought to be a crucial factor that regulates immune responses,which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis(RA).The results of our group in recent years have shown that CP-25,a novel ester derivative of paeoniflorin,has a good effect on improving RA animal models.However,whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear.METHODS CP-25 treatment ameliorated adjuvant-induced arthritis(AA),a mouse model of RA,by inhibiting Ahr-related activities in fibroblasts like synoviocytes(FLS).AA rats were treated with CP-25 or paroxetine from day 17 to 33 after immunization.RESULTS CP-25 alleviated arthritis symptoms and the pathological changes,decreased the expression of Ahr in the synovium and FLS of AA rats.Besides,treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation.In addition,we also demonstrated that CP-25 down-regulated the co-expression and co-localization of Ahr and G protein-coupled receptor kinase 2(GRK2)in MH7A.CONCLUSION The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA,which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.
