PI3K/AKT信号通路在类风湿关节炎发病机制中的研究进展
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摘要
类风湿关节炎(RA)是一种以关节滑膜炎症为特征的慢性自身免疫性疾病,其病因繁杂且累及全身多系统,参与病变过程的细胞及细胞因子众多,所以发病机制未明,治疗棘手,预后不良。PI3K/AKT信号通路是重要的细胞内信号转导通路,与RA的发生发展密切相关。近年来靶向PI3K/AKT信号通路的药物被大量研究,为广泛应用于临床治疗奠定了理论及实验基础。因此,深入明确PI3K/AKT信号通路在RA发病过程中的作用很有必要。本文中作者就PI3K/AKT信号通路在类风湿关节炎发病机制中的研究进展作一综述。
引文
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[6]GANESAN R.Fibroblast-like synoviocytes-dependent effector molecules as a critical mediator for rheumatoid arthritis:current status and future directions[J].International Reviews of Immunology,2017,36(1):20-30.
[7]FESSLER J,HUSIC R,SCHWETZ V,et al.Senescent T-cells promote bone loss in rheumatoid arthritis[J].Frontiers in Immunology,2018,9:95.
[8]WU S,LI Y,YAO L,et al.Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes[J].Clinical and Experimental Rheumatology,2018,36(2):223-227.
[9]PFEIFLE R,ROTHE T,IPSEIZ N,et al.Regulation of autoantibody activity by the IL-23-T17 axis determines the onset of autoimmune disease[J].Nature Immunology,2017,18(1):104-113.
[10]ITO Y,HART J R.Isoform-specific activities of the regulatory subunits of phosphatidylinositol 3-kinases-potentially novel therapeutic targets[J].Expert Opinion on Therapeutic Targets,2018,22(10):869-877.
[11]WU J H,TIAN X Y,AN Q M,et al.LINC00963 promotes hepatocellular carcinoma progression by activating PI3K/AKTpathway[J].European Review for Medical and Phar Macological Sciences,2018,22(6):1645-1652.
[12]QU Y,WU J,DENG J X,et al.MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K/AKT signal pathway[J].Oncotarget,2016,7(45):74217-74226.
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[14]TSAI C H,LIU S C,WANG Y H,et al.Osteopontin inhibition of mi R-129-3p enhances IL-17 expression and monocyte migration in rheumatoid arthritis[J].Biochimica et Biophysica Acta,2017,1861(2):15-22.
[15]SHODA H,NAGAFUCHI Y,TSUCHIDA Y,et al.Increased serum concentrations of IL-1 beta,IL-21 and Th17 cells in overweight patients with rheumatoid arthritis[J].ARthritis Research&Therapy,2017,19(1):111.
[16]KWOK S K,CHO M L,Park M K,et al.Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis[J].Arthritis and Rheumatism,2012,64(3):740-751.
[17]XING R,JIN Y,SUN L,et al.Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis[J].Clinical and Experimental Immunology,2016,184(2):147-158.
[18]XING R,YANG L,JIN Y,et al.Interleukin-21 induces proliferation and proinflammatory cytokine profile of fibroblast-like synoviocytes of patients with rheumatoid arthritis[J].Scandinavian Journal of Immunology,2016,83(1):64-71.
[19]DINESH P.Berberine inhibits IL-21/IL-21R mediated inflammatory proliferation of fibroblast-like synoviocytes through the attenuation of PI3K/Akt signaling pathway and ameliorates IL-21 mediated osteoclastogenesis[J].Cytokine,2018,106:54-66.
[20]MITRA A,RAYCHAUDHURI S K.IL-22 induced cell proliferation is regulated by PI3K/Akt/m TOR signaling cascade[J].Cytokine,2012,60(1):38-42.
[21]陈红梅,王友莲.破骨细胞在类风湿关节炎致骨破坏病理变化中的作用及其调控[J].中国骨质疏松杂志,2016,22(9):1168-1173.
[22]徐子涵,商玮,蔡辉.破骨细胞在类风湿关节炎骨侵蚀中的研究进展[J].现代医学,2017,36(3):446-450.
[23]WU L,GUO Q,YANG J.Tumor necrosis factor alpha promotes osteoclast formation via pi3k/akt pathway-mediated blimp1 expression upregulation[J].Journal of Cellular Biochemistry,2017,118(6):1308-1315.
[24]CHOE J Y,HUN KIM J,Park K Y,et al.Activation of dickkopf-1 and focal adhesion kinase pathway by tumour necrosis factorαinduces enhanced migration of fibroblast-like synoviocytes in rheumatoid arthritis[J].Rheumatology(Oxford,England),2016,55(5):928-938.
[25]LIACINI A,SYLVESTER J,LI W Q,et al.Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases,AP-1,and NF-kappa B transcription factors in articular chondrocytes[J].Experimental Cell Research,2003,288(1):208-217.
[26]XUAN W,FENG X,QIAN C,et al.Osteoclast differentiation gene expression profiling reveals chemokine CCL4 mediates RANKL-induced osteoclast migration and invasion via PI3Kpathway[J].Cell Biochemistry and Function,2017,35(3):171-177.
[27]YU R H,ZHAO J X.Role of hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis[J].Journal of Peking U-niversity.Health Sciences,2016,48(6):1095-1099.
[28]QUINONEZ-FLORES C M,GONZALEZ-CHAVEZ S A.Hypoxia and its implications in rheumatoid arthritis[J].Journal of Biomedical Science,2016,23(1):62.
[29]WANG C H,CHEN L N,ZHU P,et al.CD147 stimulates the angiogenesis in rheumatoid synovium via the activation of vascular endothelial growth factor[J].Chinese Journal of Cellular and Molecular Immunology,2007,23(5):426-428.
[30]ZOU L,ZHANG G,LIU L,et al.Relationship between PI3Kpathway and angiogenesis in CIA rat synovium[J].American Journal of Translational Research,2016,8(7):3141-3147.
[31]YANG Z,CAO J,YU C,et al.Caspase-1 mediated interleukin-18 activation in neutrophils promotes the activity of rheumatoid arthritis in a NLRP3 inflammasome independent manner[J].Joint,Bone,Spine:Revue du Rhumatisme,2016,83(3):282-289.
[32]TIAN J,CHEN J W,GAO J S,et al.Resveratrol inhibits TNF-α-induced IL-1β,MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway[J].Rheumatology International,2013,33(7):1829-1835.
[33]XU B,WANG G,ZHANG J,et al.Resveratrol decreases Fo XO protein expression through PI3K/AKT-dependent pathway inhibition in H2O2-treated synoviocytes[J].Histology and Histopathology,2017,32(12):1305-1315.
[34]SU C M,LEE W L,HSU C J,et al.Adiponectin induces oncostatin M expression in osteoblasts through the PI3K/Akt signaling pathway[J].International Journal of Molecular Sciences,2015,17(1):29.
[35]ZHANG W,DU Z,ZHU J,et al.Sprouty2 suppresses the inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes through regulating the Raf/ERK and PTEN/AKTsignals[J].Molecular Immunology,2015,67(2PtB):532-539.
[36]BARTOK B,BOYLE D L,LIU Y,et al.PI3 kinaseδis a key regulator of synoviocyte function in rheumatoid arthritis[J].The American Journal of Pathology,2012,180(5):1906-1916.
[37]CHANG J H,LEE K J,KIM S K,et al.Validity of SW982synovial cell line for studying the drugs against rheumatoid arthritis in fluvastatin-induced apoptosis signaling model[J].The Indian Journal of Medical Research,2014,139(1):117-124.
[38]MENG Q,DU X,WANG H,et al.Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/m TOR inhibition[J].Apoptosis:an International Journal on Programmed Cell Death,2017,22(9):1138-1146.
[2]OKADA Y,WU D,TRYNKA G,et al.Genetics of rheumatoid arthritis contributes to biology and drug discovery[J].Nature,2014,506(7488):376-381.
[3]KALLBERG H,DING B,PADYUKOV L,et al.Smoking is a major preventable risk factor for rheumatoid arthritis:estimations of risks after various exposures to cigarette smoke[J].Annals of the Rheumatic Diseases,2011,70(3):508-511.
[4]KONIG M F,ABUSLEME L,REINHOLDT J,et al.Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis[J].Sci Transl Med,2016,8:369ra176.
[5]MIAO C G,YANG Y Y,HE X,et al.Wnt signaling pathway in rheumatoid arthritis,with special emphasis on the different roles in synovial inflammation and bone remodeling[J].Cellular Signalling,2013,25(10):2069-2078.
[6]GANESAN R.Fibroblast-like synoviocytes-dependent effector molecules as a critical mediator for rheumatoid arthritis:current status and future directions[J].International Reviews of Immunology,2017,36(1):20-30.
[7]FESSLER J,HUSIC R,SCHWETZ V,et al.Senescent T-cells promote bone loss in rheumatoid arthritis[J].Frontiers in Immunology,2018,9:95.
[8]WU S,LI Y,YAO L,et al.Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes[J].Clinical and Experimental Rheumatology,2018,36(2):223-227.
[9]PFEIFLE R,ROTHE T,IPSEIZ N,et al.Regulation of autoantibody activity by the IL-23-T17 axis determines the onset of autoimmune disease[J].Nature Immunology,2017,18(1):104-113.
[10]ITO Y,HART J R.Isoform-specific activities of the regulatory subunits of phosphatidylinositol 3-kinases-potentially novel therapeutic targets[J].Expert Opinion on Therapeutic Targets,2018,22(10):869-877.
[11]WU J H,TIAN X Y,AN Q M,et al.LINC00963 promotes hepatocellular carcinoma progression by activating PI3K/AKTpathway[J].European Review for Medical and Phar Macological Sciences,2018,22(6):1645-1652.
[12]QU Y,WU J,DENG J X,et al.MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K/AKT signal pathway[J].Oncotarget,2016,7(45):74217-74226.
[13]KIM K W,CHO M L,PARK M K,et al.Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor kappa B-dependent pathway in patients with rheumatoid arthritis[J].Arthritis Research&Therapy,2005,7(1):R139-148.
[14]TSAI C H,LIU S C,WANG Y H,et al.Osteopontin inhibition of mi R-129-3p enhances IL-17 expression and monocyte migration in rheumatoid arthritis[J].Biochimica et Biophysica Acta,2017,1861(2):15-22.
[15]SHODA H,NAGAFUCHI Y,TSUCHIDA Y,et al.Increased serum concentrations of IL-1 beta,IL-21 and Th17 cells in overweight patients with rheumatoid arthritis[J].ARthritis Research&Therapy,2017,19(1):111.
[16]KWOK S K,CHO M L,Park M K,et al.Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis[J].Arthritis and Rheumatism,2012,64(3):740-751.
[17]XING R,JIN Y,SUN L,et al.Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis[J].Clinical and Experimental Immunology,2016,184(2):147-158.
[18]XING R,YANG L,JIN Y,et al.Interleukin-21 induces proliferation and proinflammatory cytokine profile of fibroblast-like synoviocytes of patients with rheumatoid arthritis[J].Scandinavian Journal of Immunology,2016,83(1):64-71.
[19]DINESH P.Berberine inhibits IL-21/IL-21R mediated inflammatory proliferation of fibroblast-like synoviocytes through the attenuation of PI3K/Akt signaling pathway and ameliorates IL-21 mediated osteoclastogenesis[J].Cytokine,2018,106:54-66.
[20]MITRA A,RAYCHAUDHURI S K.IL-22 induced cell proliferation is regulated by PI3K/Akt/m TOR signaling cascade[J].Cytokine,2012,60(1):38-42.
[21]陈红梅,王友莲.破骨细胞在类风湿关节炎致骨破坏病理变化中的作用及其调控[J].中国骨质疏松杂志,2016,22(9):1168-1173.
[22]徐子涵,商玮,蔡辉.破骨细胞在类风湿关节炎骨侵蚀中的研究进展[J].现代医学,2017,36(3):446-450.
[23]WU L,GUO Q,YANG J.Tumor necrosis factor alpha promotes osteoclast formation via pi3k/akt pathway-mediated blimp1 expression upregulation[J].Journal of Cellular Biochemistry,2017,118(6):1308-1315.
[24]CHOE J Y,HUN KIM J,Park K Y,et al.Activation of dickkopf-1 and focal adhesion kinase pathway by tumour necrosis factorαinduces enhanced migration of fibroblast-like synoviocytes in rheumatoid arthritis[J].Rheumatology(Oxford,England),2016,55(5):928-938.
[25]LIACINI A,SYLVESTER J,LI W Q,et al.Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases,AP-1,and NF-kappa B transcription factors in articular chondrocytes[J].Experimental Cell Research,2003,288(1):208-217.
[26]XUAN W,FENG X,QIAN C,et al.Osteoclast differentiation gene expression profiling reveals chemokine CCL4 mediates RANKL-induced osteoclast migration and invasion via PI3Kpathway[J].Cell Biochemistry and Function,2017,35(3):171-177.
[27]YU R H,ZHAO J X.Role of hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis[J].Journal of Peking U-niversity.Health Sciences,2016,48(6):1095-1099.
[28]QUINONEZ-FLORES C M,GONZALEZ-CHAVEZ S A.Hypoxia and its implications in rheumatoid arthritis[J].Journal of Biomedical Science,2016,23(1):62.
[29]WANG C H,CHEN L N,ZHU P,et al.CD147 stimulates the angiogenesis in rheumatoid synovium via the activation of vascular endothelial growth factor[J].Chinese Journal of Cellular and Molecular Immunology,2007,23(5):426-428.
[30]ZOU L,ZHANG G,LIU L,et al.Relationship between PI3Kpathway and angiogenesis in CIA rat synovium[J].American Journal of Translational Research,2016,8(7):3141-3147.
[31]YANG Z,CAO J,YU C,et al.Caspase-1 mediated interleukin-18 activation in neutrophils promotes the activity of rheumatoid arthritis in a NLRP3 inflammasome independent manner[J].Joint,Bone,Spine:Revue du Rhumatisme,2016,83(3):282-289.
[32]TIAN J,CHEN J W,GAO J S,et al.Resveratrol inhibits TNF-α-induced IL-1β,MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway[J].Rheumatology International,2013,33(7):1829-1835.
[33]XU B,WANG G,ZHANG J,et al.Resveratrol decreases Fo XO protein expression through PI3K/AKT-dependent pathway inhibition in H2O2-treated synoviocytes[J].Histology and Histopathology,2017,32(12):1305-1315.
[34]SU C M,LEE W L,HSU C J,et al.Adiponectin induces oncostatin M expression in osteoblasts through the PI3K/Akt signaling pathway[J].International Journal of Molecular Sciences,2015,17(1):29.
[35]ZHANG W,DU Z,ZHU J,et al.Sprouty2 suppresses the inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes through regulating the Raf/ERK and PTEN/AKTsignals[J].Molecular Immunology,2015,67(2PtB):532-539.
[36]BARTOK B,BOYLE D L,LIU Y,et al.PI3 kinaseδis a key regulator of synoviocyte function in rheumatoid arthritis[J].The American Journal of Pathology,2012,180(5):1906-1916.
[37]CHANG J H,LEE K J,KIM S K,et al.Validity of SW982synovial cell line for studying the drugs against rheumatoid arthritis in fluvastatin-induced apoptosis signaling model[J].The Indian Journal of Medical Research,2014,139(1):117-124.
[38]MENG Q,DU X,WANG H,et al.Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/m TOR inhibition[J].Apoptosis:an International Journal on Programmed Cell Death,2017,22(9):1138-1146.