收稿日期: 2022-04-04
录用日期: 2022-06-14
网络出版日期: 2022-09-04
基金资助
国家重点研发计划(2018YFC1705203);国家中医药管理局行业专项项目(20150700107);甘肃省卫生健康委员会中医药管理局中医药项目(GZKP-2021-12)
Advances in the correlation between cytokine signal transduction inhibitors and rheumatoid arthritis
Received date: 2022-04-04
Accepted date: 2022-06-14
Online published: 2022-09-04
Supported by
National Key Research and Development Program of China(2018YFC1705203);Industry Special Project of National Administration of Traditional Chinese Medicine(20150700107);TCM Project from Administration of Traditional Chinese Medicine of Gansu Municipal Health Commission(GZKP-2021-12)
类风湿关节炎是一种以滑膜炎症、骨质破坏、血管翳形成为特征的慢性对称性疾病。炎症介质与类风湿关节炎的发病机制关系密切，且随着炎症介质水平的升降，类风湿关节炎的严重程度明显受到影响。该文回顾了近年国内外学者对细胞因子信号转导抑制因子与类风湿关节炎的相关性研究，发现作为内源性负性调节因子，细胞因子信号转导抑制因子通过阻断信号转导和转录激活因子（signal transducer and activator of transcription，STAT）的磷酸化、抑制Janus激酶（Janus kinase，JAK）活性，参与细胞内外信号转导，介导Ｔ细胞存活和分化，诱导炎症因子的转录和激活，调控多种细胞因子的产生，对体内多种免疫反应的激活起调控作用。因此，作为抗炎的中介蛋白，细胞因子信号转导抑制因子通过多种途径参与炎症反应，与类风湿关节炎的发生发展密切相关，有望成为该病诊断和预后的生物标志物。同时，该文预测与细胞因子信号转导抑制因子相关的细胞凋亡、免疫调控、软骨代谢及自噬等相关性研究可能成为未来类风湿关节炎的研究热点。进一步深入探究细胞因子信号转导抑制因子与类风湿关节炎的相关性及其机制，可能为治疗类风湿关节炎开拓新视野。
关键词： 类风湿关节炎; 细胞因子信号转导抑制因子; 炎症; JAK/STAT通路; NF-κB通路; MAPK通路
雷海桃 , 田雪梅 , 金芳全 . 细胞因子信号转导抑制因子与类风湿关节炎的相关性研究进展[J]. 上海交通大学学报（医学版）, 2022 , 42(7) : 945 -951 . DOI: 10.3969/j.issn.1674-8115.2022.07.015
Rheumatoid arthritis (RA) is a chronic symmetrical disease with synovial inflammation, bone destruction and pannus formation. Inflammatory mediators are closely related to the pathogenesis of RA, and the severity of RA is significantly affected by the promotion and demotion of inflammatory mediator levels. In this review, we have reviewed the studies about the correlation between cytokine signaling inhibitory factors and RA in recent years. We have found that cytokine signaling inhibitory factors, as endogenous negative regulators, are involved in intra- and extra-cellular signal transduction, mediating T cell survival and differentiation, inducing transcription and activation of inflammatory factors, and playing a regulatory role in the activation of various immune responses invivovia blocking the phosphorylation of signal transducer and activator of transcription (STAT) and inhibiting the activity of Janus kinase (JAK). Therefore, as an anti-inflammatory mediator protein, cytokine signaling inhibitory factors are involved in inflammatory responses via various pathways, closely related to the occurrence and development of RA, and are expected to be a biomarker for the diagnosis and prognosis for RA. Meanwhile, we predict that the study of apoptosis, immune regulation, cartilage metabolism and autophagy related to cytokine signaling inhibitors may become a research hotspot for RA in the future. Further in-depth research on the correlation and mechanism of cytokine signaling inhibitory factors and RA may widen our vision for the treatment of RA.
| 1 | CRAMER A, GALV?O I, VENTURINI DE Sá N, et al. Role of suppressor of cytokine signaling 2 during the development and resolution of an experimental arthritis[J]. Cell Immunol, 2022, 372: 104476. |
| 2 | SANTOS M R G, QUEIROZ-JUNIOR C M, MADEIRA M F M, et al. Suppressors of cytokine signaling (SOCS) proteins in inflammatory bone disorders[J]. Bone, 2020, 140: 115538. |
| 3 | DAI L R, LI Z A, LIANG W L, et al. SOCS proteins and their roles in the development of glioblastoma[J]. Oncol Lett, 2022, 23(1): 5. |
| 4 | MALEMUD C J. Negative regulators of JAK/STAT signaling in rheumatoid arthritis and osteoarthritis[J]. Int J Mol Sci, 2017, 18(3): 484. |
| 5 | LINOSSI E M, CALLEJA D J, NICHOLSON S E. Understanding SOCS protein specificity[J]. Growth Factors, 2018, 36(3/4): 104-117. |
| 6 | KEEWAN E, MATLAWSKA-WASOWSKA K. The emerging role of suppressors of cytokine signaling (SOCS) in the development and progression of leukemia[J]. Cancers (Basel), 2021, 13(16): 4000. |
| 7 | HUANG S, LIU K, CHENG A, et al. SOCS proteins participate in the regulation of innateimmune response caused by viruses[J]. Front Immunol, 2020, 11: 558341. |
| 8 | USHIKI T, HUNTINGTON N D, GLASER S P, et al. Rapid inflammation in mice lacking both SOCS1 and SOCS3 in hematopoietic cells[J]. PLoS One, 2016, 11(9): e0162111. |
| 9 | SOBAH M L, LIONGUE C, WARD A C. SOCS proteins in immunity, inflammatory diseases, and immune-related cancer[J]. Front Med, 2021, 8: 727987. |
| 10 | EHRENTRAUT S, SCHNEIDER B, NAGEL S, et al. Th17 cytokine differentiation and loss of plasticity after SOCS1 inactivation in a cutaneous T-cell lymphoma[J]. Oncotarget, 2016, 7(23): 34201-34216. |
| 11 | GUITTARD G, DIOS-ESPONERA A, PALMER D C, et al. The Cish SH2 domain is essential for PLC-γ1 regulation in TCR stimulated CD8+T cells[J]. Sci Rep, 2018, 8(1): 5336. |
| 12 | PALMER D C, GUITTARD G C, FRANCO Z, et al. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance[J]. J Exp Med, 2015, 212(12): 2095-2113. |
| 13 | 孟梅, 岳正刚, 周瑞, 等. 靶向类风湿关节炎细胞因子与信号通路的治疗药物进展[J]. 中国药学杂志, 2021, 56(8): 620-625. |
| 13 | MENG M, YUE Z G, ZHOU R, et al. Progress in therapeutic drugs targeting rheumatoid arthritis cytokines and signaling pathways[J]. Chin Pharm J, 2021, 56(8): 620-625. |
| 14 | LA MANNA S, DE BENEDICTIS I, MARASCO D. Proteomimetics of natural regulators of JAK-STAT pathway: novel therapeutic perspectives[J]. Front Mol Biosci, 2021, 8: 792546. |
| 15 | LI T, WU S Y, LI S, et al. SOCS3 participates in cholinergic pathway regulation of synovitis in rheumatoid arthritis[J]. Connect Tissue Res, 2018, 59(3): 287-294. |
| 16 | 王芬, 赵彬元, 严兴科, 等. 热补针法对类风湿关节炎大鼠滑膜细胞JAK-STAT信号通路调节因子SOCS1、SOCS3表达的影响[J]. 中国中医药信息杂志, 2020, 27(6): 56-60. |
| 16 | WANG F, ZHAO B Y, YAN X K, et al. Effects of heat-reinforcing needling on expressions of cytokine signal suppressor SOCS1 and SOCS3 in JAK-STAT pathway of synovium cells in rheumatoid arthritis rats[J]. Tradit Chin Med Inf (Chinese), 2020, 27(6): 56-60. |
| 17 | 马俊福, 孟庆良, 苗喜云, 等. 转录因子Egr2/Egr3在类风湿关节炎寒证中的作用机制[J]. 世界科学技术-中医药现代化, 2021, 23(8): 2816-2822.MA J F, MENG Q L, MIAO X Y, et al. Mechanism of transcription factor Egr2/Egr3 in cold syndrome of rheumatoid arthritis[J]. Mod Tradit Chin Med (World Sci Technol), 2021, 23(8):2816-2822. |
| 18 | SONI B, SINGH S. Synthetic perturbations in IL6 biological circuit induces dynamica cellular response[J]. Molecules, 2021, 27(1): 124. |
| 19 | GAO Y, ZHAO H L, WANG P, et al. The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases[J]. Scand J Immunol, 2018, 88(6): e12727. |
| 20 | MASOOD K I, IRFAN M, MASOOD Q, et al. Latent M. tuberculosis infection is associated with increased inflammatory cytokine and decreased suppressor of cytokine signalling (SOCS)-3 in the diabetic host[J]. Scand J Immunol, 2022, 95(4): e13134. |
| 21 | BAI X Y, LIU P, CHAI Y W, et al. Artesunate attenuates 2, 4-dinitrochlorobenzene-induced atopic dermatitis by down-regulating Th17 cell responses in BALB/c mice[J]. Eur J Pharmacol, 2020, 874: 173020. |
| 22 | DONG X, ZHANG X, XU S, et al. SOCS-1 suppresses neuroinflammation in intracranial hemorrhage by downregulating the c-Fos/KLF4/IL-17A axis[J]. Eur J Neurosci, 2022. DOI: 10.1111/ejn.15615. |
| 23 | DUNCAN S A, DIXIT S, SAHU R, et al. Prolonged release and functionality of interleukin-10 encapsulated within PLA-PEG nanoparticles[J]. Nanomaterials (Basel), 2019, 9(8): 1074. |
| 24 | 张飘, 龙立书, 洪猛, 等. JAK-STAT信号通路Jak2、Stat3和Socs1基因在鸭肠炎病毒感染中各组织的表达变化[J]. 中国兽医学报, 2021, 41(7): 1335-1347. |
| 24 | ZHANG P, LONG L S, HONG M, et al. Changes of expression of Jak2, Stat3 and Socs1 genes in JAK-STAT signaling pathway in various tissues of duck infected with duck enteritis virus[J]. Chin J Vet Sci, 2021, 41(7): 1335-1347. |
| 25 | RUGANZU J B, ZHENG Q Z, WU X Y, et al. TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway[J]. Exp Neurol, 2021, 336: 113506. |
| 26 | 张传英, 邵芙蓉, 蔡荣林, 等. 艾灸对类风湿性关节炎大鼠关节滑膜组织转录信号转导因子1、细胞因子信号负调控因子基因表达的影响[J]. 针刺研究, 2015, 40(3): 205-209. |
| 26 | ZHANG C Y, SHAO F R, CAI R L, et al. Effects of moxibustion on expression of STAT1, SOCS mRNA in synovium of rats with rheumation arthritis[J]. Acupunct Res, 2015, 40(3): 205-209. |
| 27 | WAIBOCI L W, AHMED C M, MUJTABA M G, et al. Both the suppressor of cytokine signaling 1 (SOCS-1) kinase inhibitory region and SOCS-1 mimetic bind to JAK2 autophosphorylation site: implications for the development of a SOCS-1 antagonist[J]. J Immunol, 2007, 178(8): 5058-5068. |
| 28 | SCHINOCCA C, RIZZO C, FASANO S, et al. Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview[J]. Front Immunol, 2021, 12: 637829. |
| 29 | 葛改, 杨智雅, 张祥宇, 等. SOCS通过调控JAK/STAT通路影响Th细胞分化在感染性疾病中的作用研究进展[J]. 中国真菌学杂志, 2021, 16(1): 51-55. |
| 29 | GE G, YANG Z Y, ZHANG X Y, et al. Research progress on the effect of SOCS on Th cell differentiation in infectious diseases by regulating JAK/STAT pathway[J]. Chin J Mycol, 2021, 16(1): 51-55. |
| 30 | TAKAHASHI R, NAKATSUKASA H, SHIOZAWA S, et al. SOCS1 is a key molecule that prevents regulatory T cell plasticity under inflammatory conditions[J]. J Immunol, 2017, 199(1): 149-158. |
| 31 | YAMANA J, YAMAMURA M, OKAMOTO A, et al. Resistance to IL-10 inhibition of interferon gamma production and expression of suppressor of cytokine signaling 1 in CD4+ T cells from patients with rheumatoid arthritis[J]. Arthritis Res Ther, 2004, 6(6): R567-R577. |
| 32 | LIANG Y, XU W D, PENG H, et al. SOCS signaling in autoimmune diseases: molecularmechanisms and therapeutic implications[J]. Eur J Immunol, 2014, 44(5): 1265-1275. |
| 33 | 林婉娜, 苏慧琳, 李慧敏, 等. 黄芪桂枝五物汤抗类风湿性关节炎的作用机制[J]. 中国实验方剂学杂志, 2022, 28(9): 9-15. |
| 33 | LIN W N, SU H L, LI H M, et al, Therapeutic mechanism of Huangqi Guizhi Wuwutang on rheumatoid arthritis[J]. Chin J Exp Formul, 2022, 28(9): 9-15. |
| 34 | LETELLIER E, HAAN S. SOCS2: physiological and pathological functions[J]. Front Biosci (Elite Ed), 2016, 8(1): 189-204. |
| 35 | CHEN Y H, SHIN J Y, WEI H M, et al. Prevention of dextran sulfate sodium-induced mouse colitis by the fungal protein Ling Zhi-8 via promoting the barrier function of intestinal epithelial cells[J]. Food Funct, 2021, 12(4): 1639-1650. |
| 36 | OH J, KIM S H, AHN S, et al. Suppressors of cytokine signaling promote Fas-induced apoptosis through downregulation of NF-κB and mitochondrial Bfl-1 in leukemic T cells[J]. J Immunol, 2012, 189(12): 5561-5571. |
| 37 | 孙婷, 陈泉, 肖继, 等. NF-κB亚基泛素化研究进展[J]. 生理科学进展, 2018, 49(3): 217-221. |
| 37 | SUN T, CHEN Q, XIAO J, et al. The progress in ubiquitination of NF-KB subunits[J]. Prog in Physiol Sci, 2018, 49(3): 217-221. |
| 38 | Pi?eros Alvarez A R, Glosson-Byers N, Brandt S, et al. SOCS1 is a negative regulatorof metabolic reprogramming during sepsis[J]. JCI Insight, 2017, 2(13): e92530. |
| 39 | YONG Y H, WANG P, JIA R M, et al. SOCS3 control the activity of NF-κB induced by HSP70 via degradation of MyD88-adapter-like protein (Mal) in IPEC-J2 cells[J]. Int J Hyperth, 2019, 36(1): 151-159. |
| 40 | 刘丹华, 张瑞莉, 田旭, 等. 黄芪多糖在LPS诱导的DF-1细胞炎症反应中的抗炎作用及其调节机制[J]. 中国兽医学报, 2021, 41(1): 143-149. |
| 40 | LIU D H, ZHANG R L, TIAN X, et al. Anti-inflammatory effect of Astragalus polysaccharides on LPS-induced DF-1 cell inflammation and its regulatory mechanism[J]. Chin J of Vet Sci, 2021, 41(1): 143-149. |
| 41 | GEORGANA I, MALUQUER DE MOTES C. Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of multiple signaling pathways[J]. Front Immunol, 2019, 10: 3121. |
| 42 | LI S, HAN S, JIN K P, et al. SOCS2 suppresses inflammation and apoptosis during NASH progression through limiting NF-κB activation in macrophages[J]. Int J Biol Sci, 2021, 17(15): 4165-4175. |
| 43 | LI J Y, SUN Q, ZHENG C Y, et al. Lipoxin A4-mediated p38 MAPK signaling pathway protects mice against collagen-induced arthritis[J]. Biochem Genet, 2021, 59(1): 346-365. |
| 44 | NOSRATPOUR S, NDIAYE K. Ankyrin-repeat and SOCS box-containing protein 9 (ASB9) regulates ovarian granulosa cells function and MAPK signaling[J]. Mol Reprod Dev, 2021, 88(12): 830-843. |
| 45 | 陶新磊, 刘丹华, 田旭, 等. 黄芪多糖诱导SOCS3表达对鸡巨噬细胞炎症反应的抑制作用[J]. 中国畜牧兽医, 2021, 48(11): 4284-4291. |
| 45 | TAO X L, LIU D H, TIAN X, et al. Inhibitory effect of Astragalus polysaccharide on inflammatory response of chicken macrophages by inducing SOCS3 expression[J]. Chin Anim Husban Vet, 2021, 48(11): 4284-4291. |
| 46 | FENG S, WANG J F, XU X Q, et al. The expression of SOCS and NF-κB p65 in hypopharyngeal carcinoma[J]. Iran J Public Heal, 2018, 47(12): 1874-1882. |
| 47 | SAHAY B, PATSEY R L, EGGERS C H, et al. CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance[J]. PLoS Pathog, 2009, 5(12): e1000687. |
| 48 | VUKMAN K V, ADAMS P N, O'NEILL S M. Fasciola hepatica tegumental coat antigen suppresses MAPK signalling in dendritic cells and up-regulates the expression of SOCS3[J]. Parasite Immunol, 2013, 35(7/8): 234-238. |
| 49 | VEENBERGEN S, BENNINK M B, AFFANDI A J, et al. A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis[J]. Ann Rheum Dis, 2011, 70(12): 2167-2175. |
| 50 | YU C F, PENG W M, SCHLEE M, et al. SOCS1 and SOCS3 target IRF7 degradation to suppress TLR7-mediated typeⅠIFN production of human plasmacytoid dendritic cells[J]. J Immunol, 2018, 200(12): 4024-4035. |
| 51 | SPRINGER J M, RAVEENDRAN V V, ZHANG M C, et al. Mast cell degranulation decreases lipopolysaccharide-induced aortic gene expression and systemic levels of interleukin-6 in vivo[J]. Mediat Inflamm, 2019, 2019: 3856360. |
| 52 | CASTILLO J A, GIRALDO D M, HERNANDEZ J C, et al. Regulation of innate immune responses in macrophages differentiated in the presence of vitamin D and infected with dengue virus 2[J]. PLoS Neglected Trop Dis, 2021, 15(10): e0009873. |
| 53 | MARIJNISSEN R J, ROELEVELD D M, YOUNG D, et al. Interleukin-21 receptor deficiency increases the initial toll-like receptor 2 response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis[J]. Arthritis Rheumatol Hoboken N J, 2014, 66(4): 886-895. |
| 54 | CHE MAT N F, SIDDIQUI S, MEHTA D, et al. Lymphocytic choriomeningitis virus infection of dendritic cells interferes with TLR-induced IL-12/IL-23 cytokine production in an IL-10 independent manner[J]. Cytokine, 2018, 108: 105-114. |
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