脾淋巴细胞β_2肾上腺素受体激活参与佐剂性关节炎大鼠抗体的产生及木瓜苷对其的影响
|
摘要
类风湿关节炎(rheumatoid arthritis, RA)是一种慢性、炎性、系统性的自身免疫性疾病,病理表现多种多样。在RA的发病过程中不仅有T细胞参与,同时伴有B细胞高度活化,患者血清中可出现多种自身抗体,导致组织和器官的损伤。RA患者体内存在的自身抗体如抗角蛋白抗体(antikeratin antibody, AKA),类风湿因子(rheumatoid factor, RF)等是自身免疫疾病的重要标志。这些特异性抗体与其相应的抗原形成抗原抗体复合物,激活补体系统,触发一系列的自身免疫反应。日益增多的研究表明:自身抗体的产生在RA的病程中发挥着重要的作用。由于RA的病因和发病机制仍不甚明确,目前还没有令人满意的疗法。
木瓜苷(glucosides of chaenomeles speciosa,GCS)是从宣木瓜中提取的有效部位。本课题组前期研究表明,GCS具有较强的抗炎镇痛作用,对大鼠佐剂性关节炎(adjuvant arthritis, AA)和胶原性关节炎(collagen-induced arthritis, CIA)均有不同程度的预防和治疗作用。GCS对大鼠关节炎的治疗作用与其调节大鼠滑膜细胞和肠淋巴细胞的鸟苷酸结合蛋白(Guanine nucleotide-binding proteins,简称G蛋白)偶联的信号转导有关。脾脏是机体最大的外周淋巴器官,其中B细胞约占60%。B细胞在抗原刺激下转化为浆细胞,继而分泌特异性免疫球蛋白,同时发挥抗原提呈作用,是体液免疫的基础。β2-肾上腺素受体(β2-adrenergic receptor,β2AR)是一类在免疫应答过程中发挥重要作用的G蛋白偶联受体(G protein-coupled receptors, GPCRs),其异常表达影响免疫细胞的功能,参与疾病的发生和发展。本研究采用大鼠AA模型,观察GCS对AA大鼠继发侧足爪肿胀度和脾脏病理形态学的影响,首次研究GCS对AA大鼠血清抗体水平的影响及机制;以脾淋巴细胞(spleen lymphocytes, SLC)为实验对象,首次探讨GCS对AA大鼠SLC cAMP水平和β2AR表达的影响,分析SLCβ2AR-G蛋白-cAMP信号转导在GCS下调AA大鼠抗体产生中的作用。
目的:
实验通过观察GCS对AA大鼠足爪肿胀、脾脏病理形态学改变的改善作用,阐述GCS对AA大鼠脾脏功能的影响;通过检测大鼠血清抗体水平SLC cAMP水平和β2AR表达情况,阐述SLCβ2AR-G蛋白-cAMP信号转导在GCS下调AA大鼠抗体产生中的作用。
方法:
大鼠足趾皮内注射完全弗氏佐剂(Freund’s completed adjuvant, FCA)诱发大鼠AA模型;以GCS(30、60、120 mg·kg-1)治疗给药(ig,d17-d24),雷公藤多苷(GTW,40 mg·kg-1)作为阳性对照。足容积法测量继发侧足肿胀、进行多发性关节评分并记录脾脏指数的变化;光学显微镜观察脾脏病理学变化;聚乙二醇(PEG)6000沉淀法检测血清循环免疫复合物(circulating immune complexes,CIC);酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测血清中抗Ⅱ型胶原抗体(anti- CⅡantibody)水平和抗结核杆菌抗体(anti-TB antibody)水平;放射性免疫法测定SLC产生的cAMP水平;免疫组化法动态检测脾脏β2AR蛋白的表达;Western blot法检测SLCβ2AR蛋白的表达水平。
结果:
1. GCS缓解AA大鼠关节肿胀和脾脏炎症与其下调血清抗体水平相关
GCS(30、60、120mg·kg-1)治疗给药(ig,d17-d24)可不同程度减轻AA大鼠关节肿胀度,改善AA大鼠脾脏炎症和病理变化,其中GCS(120 mg·kg-1, ig,d17-d24)改善最为显著;GCS(60、120 mg·kg-1)可明显降低脾脏指数。
AA大鼠血清循环免疫复合物(circulating immune complexes,CIC)水平、血清中抗Ⅱ型胶原抗体(anti- CⅡantibody)和抗结核杆菌抗体(anti-TB antibody)水平显著升高,GCS(60、120 mg·kg--1,ig,d17-d24)体内给药可明显降低血清中升高的抗体水平。相关性分析显示,GCS缓解AA大鼠关节肿胀与其降低血清抗体水平密切相关。
2. GCS下调血清抗体水平与其降低SLC胞内升高的cAMP水平相关AA大鼠SLC产生的cAMP水平明显高于正常大鼠,GCS(60、120mg·kg-1)治疗给药(ig,d17-d24)可进一步降低AA大鼠SLC胞内升高的cAMP水平,相关性分析显示,GCS下调血清抗体水平与其降低SLC胞内升高的cAMP水平密切相关,提示GCS调节AA大鼠SLC胞内cAMP水平是其下调AA大鼠血清抗体水平,发挥治疗作用的特点之一。
3. AA大鼠SLCβ2AR的表达情况及GCS的调节作用采用免疫组化和Western blot法检测SLC的β2AR蛋白表达水平。AA大鼠致敏后,SLC中β2AR表达水平显著降低,提示SLCβ2AR参与AA的发病过程。GCS(60、120mg·kg-1,ig,d17-d24)能明显上调β2AR的表达。这一结果提示GCS通过调节SLCβ2AR-G蛋白-cAMP的信号转导通路下调AA大鼠抗体产生。
结论:
1. GCS对AA大鼠关节肿胀和脾脏病理学形态的改变具有明显的改善作用;GCS能显著下调血清抗体水平。
2.降低AA大鼠SLC升高的cAMP水平是GCS下调血清抗体水平的重要特点之一。
3. GCS可上调SLC的β2AR蛋白表达水平,恢复AA大鼠SLC的β2AR-G蛋白-cAMP信号的正常转导可能是GCS下调抗体水平的部分机制。
Rheumatoid arthritis(RA) is a chronic,inflammatory and systemic autoimmune disease. In Addition to the participation of T lymphocyte, B lymphocyte is severe activated durning the development and pathogenesis of RA.The autoantibodies in serum such as antikeratin antibody(AKA)and rheumatoid factor(RF) which is the significant identification for autoimmune diseases contribute to the damages of tissues and organics.The autoantibodies combine with reciprocal antigen into antigen antibody complexes,which then activate complement system and trigger a trail of autoimmune responses.Growing investigations suggest that autoantibodies play an important role in the development and pathogenesis of RA.Due to the unclearness etiopathogenisis of RA,there is no satisfactory treatments and strategies for RA at present.
Chaenomeles speciosa (sweet) Nakai is one of the valuable traditional herbs used in treatment for RA with a long history in traditional Chinese medicine.Glucosides of Chaenomeles speciosa(GCS),extracted from the fructus of Chaenomeles speciosa,is an active compound. Our previous studies have showed that GCS had preventive and therapetic effects on rats with collagen-induced arthritis (CIA) and adjuvant arthritis(AA).The therapetic effects of GCS on rat with arthritis related to the G-protein coupled signal transduction pathway.Spleen is the most biggest lymphatic organ in which about 60 percent of B lymphocyte. B lymphocyte is the foundation of humoral immunity where antigen is presented and antibody is secreted.
Beta 2-adrenergic receptor(β2AR) is an important GPCR in the inflammatory responses,which contributes to the development and growth of RA in the presence of its abnormal expression.The present study show that the effects of GCS on the secondary inflammatory and pathomorphology of spleen in rats with AA.In addition,we assay the autoantibodies in serum and examine the expression ofβ2AR in spleen lymphocytes(S LC).This study designs to investigateβ2AR-AC-cAMP transmembrane signal transduction of SLC and the effect of GCS on downregulating the level of serum antibodies..
OBJECTIVE
According to the changes of paw swelling, histological morphological of spleen and the levels of serum autoantibodies, this study tends to clarify the influences of spleen functions and therapeutic effects of GCS in rats with AA. To further investigate the downregulating effects of GCS on the level of autoantibodies and cAMP of SLC,we examine the expression ofβ2AR of SLC and explore the latent mechanisms of GCS on downregulating the level of serum antibodies by regulating pathway ofβ2AR-AC-cAM P transmembrane signal transduction of SLC.
METHODS
Freund’s complete adjuvant (FCA) was used to induced AA in rats.Rats were divided into six groups and administrated intragastrically with GCS(30,60,120mg·kg-1, d17-d24) after immunization and GTW(40 mg·kg-1,d17-d24) as positive control groups. And for the groups of normal and AA,rats were given an equal volume of vehicle(CMC-Na) at the same time.
Secondary paw swelling of AA rats were measured with volume meter; Histopathological change of spleen was observed by light microscope; The level of circulating immune complexes in serum was determined by PEG6000 assay, while the levels of anti- CⅡantibody, and anti-TB antibody in serum were measured by enzyme-linked immunosorbent assay(ELISA), the level of cAMP in SLC was measured by radioimmunoassay,respectively; The expression ofβ2AR on SLC were detected by Western blot and immunohistochemistry analysis.
RESUILTS
1. The effects of GCS on relieving joints swelling and inflammation of spleens in rats with AA were correlated with its effects on downregulating the levels of serum autoantibodies
It was found that GCS(60,120mg·kg-1,ig,d17-d24) significantly suppressed secondary hind paw swelling ,polyarthritis index and spleen index,as well as ameliorated arthritic status histological of spleens in rats with AA.
GCS(60,120mg·kg-1,ig,d17-d24) significantly downregulated the levels of CIC, anti-CⅡantibody and anti-TB antibody in serum in rats with AA.The correlation analysis demonstrated that the effect of GCS on reliefing the joint swelling of AA rats was correlated intimately with its effect on downregulating the levels of autoantibodies in serum.
2. The effects of GCS on downregulating the levels of serum autoantibodies in rats with AA were correlated with its effects on decreasing the elevated level of cAMP in SLC
GCS(60,120mg·kg-1,ig,d17-d24) significantly diminished the level of cAMP in SLC.The correlation analysis demonstrated that the effect of GCS on downregulating the level of cAMP in rats with AA was correlated intimately with its effect on decreasing the level of cAMP in SLC.
3. The expression ofβ2AR on SLC in rats with AA and the regulating effects of GCS
The results of Western blot and immunohistochemistry demonstrated that GCS increased the lowered expression ofβ2AR in SLC markly.The results suggested that GCS inhibited the production of autoantibodies by modulatingβ2AR-AC-cAMP transmembrane signal transduction pathway of SLC.
CONCLUSIONS
1.GCS surpresses the secondary paw swelling and ameliorates the spleen inflammation while accompany with downregulating the autoantibodies in serum.
2. GCS diminishes the elevated level of cAMP in SLC,which is one of the most important characteristics of therapetic effects of GCS.
3. GCS upregulated the lowered expression ofβ2AR in SLC,which suggested that GCS might prevent rats from the production of autoantibodies by recovering the pathway ofβ2AR-AC-cAMP normal transmembrane signal transduction of SLC.
木瓜苷(glucosides of chaenomeles speciosa,GCS)是从宣木瓜中提取的有效部位。本课题组前期研究表明,GCS具有较强的抗炎镇痛作用,对大鼠佐剂性关节炎(adjuvant arthritis, AA)和胶原性关节炎(collagen-induced arthritis, CIA)均有不同程度的预防和治疗作用。GCS对大鼠关节炎的治疗作用与其调节大鼠滑膜细胞和肠淋巴细胞的鸟苷酸结合蛋白(Guanine nucleotide-binding proteins,简称G蛋白)偶联的信号转导有关。脾脏是机体最大的外周淋巴器官,其中B细胞约占60%。B细胞在抗原刺激下转化为浆细胞,继而分泌特异性免疫球蛋白,同时发挥抗原提呈作用,是体液免疫的基础。β2-肾上腺素受体(β2-adrenergic receptor,β2AR)是一类在免疫应答过程中发挥重要作用的G蛋白偶联受体(G protein-coupled receptors, GPCRs),其异常表达影响免疫细胞的功能,参与疾病的发生和发展。本研究采用大鼠AA模型,观察GCS对AA大鼠继发侧足爪肿胀度和脾脏病理形态学的影响,首次研究GCS对AA大鼠血清抗体水平的影响及机制;以脾淋巴细胞(spleen lymphocytes, SLC)为实验对象,首次探讨GCS对AA大鼠SLC cAMP水平和β2AR表达的影响,分析SLCβ2AR-G蛋白-cAMP信号转导在GCS下调AA大鼠抗体产生中的作用。
目的:
实验通过观察GCS对AA大鼠足爪肿胀、脾脏病理形态学改变的改善作用,阐述GCS对AA大鼠脾脏功能的影响;通过检测大鼠血清抗体水平SLC cAMP水平和β2AR表达情况,阐述SLCβ2AR-G蛋白-cAMP信号转导在GCS下调AA大鼠抗体产生中的作用。
方法:
大鼠足趾皮内注射完全弗氏佐剂(Freund’s completed adjuvant, FCA)诱发大鼠AA模型;以GCS(30、60、120 mg·kg-1)治疗给药(ig,d17-d24),雷公藤多苷(GTW,40 mg·kg-1)作为阳性对照。足容积法测量继发侧足肿胀、进行多发性关节评分并记录脾脏指数的变化;光学显微镜观察脾脏病理学变化;聚乙二醇(PEG)6000沉淀法检测血清循环免疫复合物(circulating immune complexes,CIC);酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测血清中抗Ⅱ型胶原抗体(anti- CⅡantibody)水平和抗结核杆菌抗体(anti-TB antibody)水平;放射性免疫法测定SLC产生的cAMP水平;免疫组化法动态检测脾脏β2AR蛋白的表达;Western blot法检测SLCβ2AR蛋白的表达水平。
结果:
1. GCS缓解AA大鼠关节肿胀和脾脏炎症与其下调血清抗体水平相关
GCS(30、60、120mg·kg-1)治疗给药(ig,d17-d24)可不同程度减轻AA大鼠关节肿胀度,改善AA大鼠脾脏炎症和病理变化,其中GCS(120 mg·kg-1, ig,d17-d24)改善最为显著;GCS(60、120 mg·kg-1)可明显降低脾脏指数。
AA大鼠血清循环免疫复合物(circulating immune complexes,CIC)水平、血清中抗Ⅱ型胶原抗体(anti- CⅡantibody)和抗结核杆菌抗体(anti-TB antibody)水平显著升高,GCS(60、120 mg·kg--1,ig,d17-d24)体内给药可明显降低血清中升高的抗体水平。相关性分析显示,GCS缓解AA大鼠关节肿胀与其降低血清抗体水平密切相关。
2. GCS下调血清抗体水平与其降低SLC胞内升高的cAMP水平相关AA大鼠SLC产生的cAMP水平明显高于正常大鼠,GCS(60、120mg·kg-1)治疗给药(ig,d17-d24)可进一步降低AA大鼠SLC胞内升高的cAMP水平,相关性分析显示,GCS下调血清抗体水平与其降低SLC胞内升高的cAMP水平密切相关,提示GCS调节AA大鼠SLC胞内cAMP水平是其下调AA大鼠血清抗体水平,发挥治疗作用的特点之一。
3. AA大鼠SLCβ2AR的表达情况及GCS的调节作用采用免疫组化和Western blot法检测SLC的β2AR蛋白表达水平。AA大鼠致敏后,SLC中β2AR表达水平显著降低,提示SLCβ2AR参与AA的发病过程。GCS(60、120mg·kg-1,ig,d17-d24)能明显上调β2AR的表达。这一结果提示GCS通过调节SLCβ2AR-G蛋白-cAMP的信号转导通路下调AA大鼠抗体产生。
结论:
1. GCS对AA大鼠关节肿胀和脾脏病理学形态的改变具有明显的改善作用;GCS能显著下调血清抗体水平。
2.降低AA大鼠SLC升高的cAMP水平是GCS下调血清抗体水平的重要特点之一。
3. GCS可上调SLC的β2AR蛋白表达水平,恢复AA大鼠SLC的β2AR-G蛋白-cAMP信号的正常转导可能是GCS下调抗体水平的部分机制。
Rheumatoid arthritis(RA) is a chronic,inflammatory and systemic autoimmune disease. In Addition to the participation of T lymphocyte, B lymphocyte is severe activated durning the development and pathogenesis of RA.The autoantibodies in serum such as antikeratin antibody(AKA)and rheumatoid factor(RF) which is the significant identification for autoimmune diseases contribute to the damages of tissues and organics.The autoantibodies combine with reciprocal antigen into antigen antibody complexes,which then activate complement system and trigger a trail of autoimmune responses.Growing investigations suggest that autoantibodies play an important role in the development and pathogenesis of RA.Due to the unclearness etiopathogenisis of RA,there is no satisfactory treatments and strategies for RA at present.
Chaenomeles speciosa (sweet) Nakai is one of the valuable traditional herbs used in treatment for RA with a long history in traditional Chinese medicine.Glucosides of Chaenomeles speciosa(GCS),extracted from the fructus of Chaenomeles speciosa,is an active compound. Our previous studies have showed that GCS had preventive and therapetic effects on rats with collagen-induced arthritis (CIA) and adjuvant arthritis(AA).The therapetic effects of GCS on rat with arthritis related to the G-protein coupled signal transduction pathway.Spleen is the most biggest lymphatic organ in which about 60 percent of B lymphocyte. B lymphocyte is the foundation of humoral immunity where antigen is presented and antibody is secreted.
Beta 2-adrenergic receptor(β2AR) is an important GPCR in the inflammatory responses,which contributes to the development and growth of RA in the presence of its abnormal expression.The present study show that the effects of GCS on the secondary inflammatory and pathomorphology of spleen in rats with AA.In addition,we assay the autoantibodies in serum and examine the expression ofβ2AR in spleen lymphocytes(S LC).This study designs to investigateβ2AR-AC-cAMP transmembrane signal transduction of SLC and the effect of GCS on downregulating the level of serum antibodies..
OBJECTIVE
According to the changes of paw swelling, histological morphological of spleen and the levels of serum autoantibodies, this study tends to clarify the influences of spleen functions and therapeutic effects of GCS in rats with AA. To further investigate the downregulating effects of GCS on the level of autoantibodies and cAMP of SLC,we examine the expression ofβ2AR of SLC and explore the latent mechanisms of GCS on downregulating the level of serum antibodies by regulating pathway ofβ2AR-AC-cAM P transmembrane signal transduction of SLC.
METHODS
Freund’s complete adjuvant (FCA) was used to induced AA in rats.Rats were divided into six groups and administrated intragastrically with GCS(30,60,120mg·kg-1, d17-d24) after immunization and GTW(40 mg·kg-1,d17-d24) as positive control groups. And for the groups of normal and AA,rats were given an equal volume of vehicle(CMC-Na) at the same time.
Secondary paw swelling of AA rats were measured with volume meter; Histopathological change of spleen was observed by light microscope; The level of circulating immune complexes in serum was determined by PEG6000 assay, while the levels of anti- CⅡantibody, and anti-TB antibody in serum were measured by enzyme-linked immunosorbent assay(ELISA), the level of cAMP in SLC was measured by radioimmunoassay,respectively; The expression ofβ2AR on SLC were detected by Western blot and immunohistochemistry analysis.
RESUILTS
1. The effects of GCS on relieving joints swelling and inflammation of spleens in rats with AA were correlated with its effects on downregulating the levels of serum autoantibodies
It was found that GCS(60,120mg·kg-1,ig,d17-d24) significantly suppressed secondary hind paw swelling ,polyarthritis index and spleen index,as well as ameliorated arthritic status histological of spleens in rats with AA.
GCS(60,120mg·kg-1,ig,d17-d24) significantly downregulated the levels of CIC, anti-CⅡantibody and anti-TB antibody in serum in rats with AA.The correlation analysis demonstrated that the effect of GCS on reliefing the joint swelling of AA rats was correlated intimately with its effect on downregulating the levels of autoantibodies in serum.
2. The effects of GCS on downregulating the levels of serum autoantibodies in rats with AA were correlated with its effects on decreasing the elevated level of cAMP in SLC
GCS(60,120mg·kg-1,ig,d17-d24) significantly diminished the level of cAMP in SLC.The correlation analysis demonstrated that the effect of GCS on downregulating the level of cAMP in rats with AA was correlated intimately with its effect on decreasing the level of cAMP in SLC.
3. The expression ofβ2AR on SLC in rats with AA and the regulating effects of GCS
The results of Western blot and immunohistochemistry demonstrated that GCS increased the lowered expression ofβ2AR in SLC markly.The results suggested that GCS inhibited the production of autoantibodies by modulatingβ2AR-AC-cAMP transmembrane signal transduction pathway of SLC.
CONCLUSIONS
1.GCS surpresses the secondary paw swelling and ameliorates the spleen inflammation while accompany with downregulating the autoantibodies in serum.
2. GCS diminishes the elevated level of cAMP in SLC,which is one of the most important characteristics of therapetic effects of GCS.
3. GCS upregulated the lowered expression ofβ2AR in SLC,which suggested that GCS might prevent rats from the production of autoantibodies by recovering the pathway ofβ2AR-AC-cAMP normal transmembrane signal transduction of SLC.
引文
1 Lapin SV, Maslianskii AL, Mazurov VI, Totolian AA. Comparative characteristics of specific autoantibodies in rheumatoid arthritis.Ter Arkh,2005;77(12):53-9
2 Aqrawal S, Misra R, Aqqarwal A. Autoantibodies in rheumatoid arth ritis:association with severity of disease in established RA. Clin Rheumatol,2007;26(2):201-4
3 Berek C. Do B cells play an important role in the pathogenesis of rheumatoid arthritis? Z Rheumatol,2005;64(6):383-8.
4 Panayi GS. B cells:a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology,2005;44(2):113-7
5 Kohm AP, Sanders VM. Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo.Pharmacol Rev,2001;53(4):487-525
6 Wahle M, Stachetzki U, Krause A, Pierer M, Hantzschel H, Baerwald CG.. Regulation of beta 2-adrenergic receptors on CD4 and CD8 positive lymphocytes by cytokines in vitro.Cytokine,2001;16(6):205-9
7 Baerwald C, Graefe C, Muhl C, Von Wichert P, Krause A. Beta 2-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatic diseases.Eur J Clin Invest,1992;22(10):42-6
8 Jon D.Levine, Terence J.Coderre, Clyde Helms, Allan I.Basbaum. Beta2-Adrenergic mechanisms in experimental arthritis. Proc.Natl.Acad.Sci.USA,1988;85:4553-6
9 Coderre TJ, Basbaum AI, Dallman MF, Helms C,Levine JD. Epinephrine exacerbates arthritis by an action at presynaptic beta 2-adrenoceptors. Neuroscience,1990;34(2): 521-3
10 Straub RH, Cutolo M. Involvement of the hypothalamic-pituitary-Adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis:viewpoint based on systemic pathogenetic role. Arthritis Rheum,2001;44(3):493-507
11张鸽,吴玉林,沈磊,王玫,吉蕊.湿迪胶囊对大鼠佐剂性关节炎作用机制的研究.中国中药杂志,2007;32(14):1432-5
12钱娴娟,赵文明,胡永秀.口服Ⅱ型胶原蛋白诱导佐剂性关节炎大鼠免疫耐受的研究.中华风湿病学杂志,2002;6(5):331-4
13 Wei W, Xu XM, Shen YX, Ding CH, Zhang AP, Xu XY. Effects of malatonin on peripheral blood lymphocyte proliferation from patients with rheumatoid arthritis and G protein-coupled cAMP signal transduction.Chin Pharmacol Bull,1998;14(6):530-2
14 Chen Q, Wei W. Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis.Int Immunopharmacol,2002;2(10):1443-9
15 Chen Q, Wei W. Effects and mechanisms of glucoside of chaenomeles speciosa on collagen-induced arthritis in rats. Int Immunopharmacol,2003;3(4):593-608
16 Zheng YQ, Wei W.Total glucosides of paeony suppressed adjuvant arthritis in rats and tntervenes cytokine-signaling between different types of synovicytes. Int Immunopharmacol,2005;5(10):1560-73
17丁长海,徐叔云,熊祖应,梅俏,戴琍明,於传斌.免疫性关节炎模型的制备.见:徐叔云,卞如濂,陈修主编.药理实验方法学,第3版,北京:人民卫生出版社,2002:920
18 Gu WZ, Brandwein R. Inhibition of typeⅡcollagen-induced arthritis in rats by triptolide.Int Immunopharmacol,1998;20(8):389-400
19刘辉主编.临床免疫学和免疫检验实验指导(供医学检验专业用),第二版,北京:人民卫生出版社,2003:50-2
20张玲玲,魏伟,严尚学,孙妩弋,岳莉,王华,吴成义,汪倪萍,李常玉.木瓜苷对小鼠胶原性关节炎的预防作用及初步机制,中国药理学通报;2004;20(1):95-100
21 Lopez-Gonzalez MA, Calvo JR, Osuna C. Synergistic action of melatonin and vasoactive intestinal peptide in stimulating cyclic AMP production in human lymphocytes. J Pineal Res,1992;12(4):174-80
22 Scott DL. Prognostic factors in early rheumatoid arthritis. Rheumatology,2000; 39(1):24-9
23 Kessel A, Rosner I, Zuckerman E, Golan TD, Toubi E. Use of antikeratin antibodies to distinguish between rheumatoid arthritis and polyarthritis associated with hepatitis C infection. J Rheumatol,2000;27(3):610-2
24 Saraux A, Berthelot JM, Devauchelle V, Bendaoud B, Chales G, Le Henaff C, Thorel JB, Hoang S, Jousse S, Baron D, Le Goff P, Youinou P. Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. J Rheumatol, 2003;30(12):2535-9
25 Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann, Smolen JS, Steiner G. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis,2005;64(12):1731-6
26 Puga Yung GL, Le TD, Roord S, Prakken B, Albani S. Heat shock protein(HSP) for immunotherapy of rheumatoid arthritis(RA). Inflamm Res,2003;52(11):443-51
27 Durai M, Gupta RS, Moudgil KD. The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis. J Immunol,2004;172(5):2795-802
28 Nguyen TT, Zlacka D, Vavrincova P, Sedlacek P, Hromadnikova I. Detection of antibodies against 60-, 65- and 70-kDa heat shock proteins in paediatric patients with various disorders using Western blotting and ELISA.Clin Chem Lab Med,2006;44(4): 442-9
29 Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St Clair EW, Tedder TF. B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol,2007;179(2):1369-80
30 Kim HR, Kim EY, Cerny J, Moudgil KD. Antibody responses to mycobacterial and self heat shock protein 65 in autoimmune arthritis: epitope specificity and implication in pathogenesis.J Immunol,2006;177(10):6634-41
31 Durai M, Kim HR, Bala KK, Moudgil KD.T cells against the pathogenic and protective epitopes of heat-shock protein 65 are crossreactive and display functionalsimilarity: novel aspect of regulation of autoimmune arthritis. J Rheumatol,2007;34(11): 2134-43.
32 Satpute SR, Soukhareva N, Scott DW, Moudgil KD. Mycobacterial HSP65-IgG -expressing tolerogenic B cells confer protection against adjuvant-induced arthritis in Lewis rats. Arthritis Rheum,2007;56(5):1490-6
33 Homandberg GA. Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Front biosci.1999;4:713-30.
34 Kohm AP, Mozaffarian A, Sanders VM. B cell Receptor- andβ2-adrenergic receptor-induced regulation of B7-2(CD86) expression in B cells.J Immunol, 2002;168(12):6314-22
35 Sanders VM. The role of norepinephrine and beta-2 adrenergic receptor stimulation in the modulation of Th1,Th2 and B lymphocyte function.Adv Exp Med Biol,1998;437:269-78
36 Podojil JR, Kin NW, Sanders VM. CD86 and beta2-adrenergic receptor signaling pathways,respectively,increase Oct-2 and OCA-B Expression and binding to the 3’-IgH enhancer in B cells.J Biol Chem,2004;279(22):23394-404
37 Ader R, Felten D, Cohen N. Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol,1990;30:561-602
38 Besedovsky HO, Del Rey A. Immune-neuro-endocrine interactions:facts and hypotheses.Endocr Rev,1996;17(1):64-102
39 Kohm AP, Sanders VM. Norepinephrine andβ2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev,2001;53(4):487-525
40 Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol,2004;5(6):575-81
41 Kin NW, Sanders VM. It takes nerve to tell T and B cells what to do. J Leukoc Biol,2006;79(6):1093-104
42 Ziemssen T, Kern S. Psychneuroimmunology-cross-talk between the immune and nervous systems. J Neurol,2007;254(2):Ⅱ8-11
43 Baerwald CG, Wahle M, Ulrichs T, Jonas D, von Bierbrauer A, von Wichert P, Burmester GR, Krause A. Reduced catecholamine response of lymphocytes from patients with rheumatoid arthritis. Immunobiology,1999;200(1):77-91
44 Wahle M, K?lker S, Krause A, Burmester GR, Baerwald CG. Impaired catecholaminergic signalling of B lymphocytes in patients with chronic rheumatic diseases. Ann Rheum Dis,2001;60(5):505-10
45 Wahle M, Krause A, Pierer M, Hantzschel H, Baerwald CG. Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions. Ann N Y Acad Sci,2002;966:355-64
46 Felten DL, Ackerman KD, Wiegand SJ, Felten SY. Noradrenergic sympathetic innervation of the spleen:1.Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J Neurosci Res,1987;18(1):28-36
47葛志东,陈敏珠,徐叔云.大鼠脾淋巴细胞β肾上腺素受体的放射配位体测定.中国药理学通报,1991;12(4):340-3
48葛志东,陈敏珠,徐叔云.交感神经对抗体应答的调控.中国药理学通报,1991;7(3): 161-4.
49葛志东,陈敏珠,徐叔云.SRBC致敏对大鼠脾脏淋巴细胞β-受体的影响.中国免疫学杂志,1991;7(6):202-4
50 Lucin KM, Sander VM, Jones TB, Malarkey WB, Popovich PG. Impaired antibodies synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation.Exp Neurol, 2007;207(1): 75-84
51 Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The symphthetic nerve-an integrative interface between two super systems:the brain and the immune system.Pharmacol Rev,2000;52(4):595-638
52 Kohm AP, Sanders VM. Norepinephrine: a messenger from the brain to the immunesystem.Immunol Today,2000;21(11):539-42
53 Kohm AP, Sanders VM. Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo.J Immunol,1999; 162(9):5299-308
54 Sanders VM. Interdisciplinary research:noradrenergic regulation of adaptive immunity.Brain Behav Immun,2006;79(6):1093-104
55 Podojil JR, Sander VM. Selective regulation of mature IgG1 transcription by CD86 and beta 2-adrenergic receptor stimulation.J Immunol,2003;170(10):5143-51
56 Premont RT, Gainetdinov RR. Physiological roles of G protein-coupled receptor kinase and arrestins. Annu Rev Physiol,2007;69:511-34
57 Siehler S. Cell-based assays in GPCR drug discovery. Biotechnol J,2008;3(4):471-83
58 Mizobe T. Cuerrent aspects of research on agrenergic receptor. Masui,2008;57(1): 22-38
59 Oostendorp J, Postma DS, Volders H, Jonquepier H, Kauffman HF, Boezen HM, Meyers DA, Bleecker ER, Nelemans SA, Zaaqsma J, Meurs H. Differential desensitization of homozygous haplotypes of the beta 2-adrenergic receptor in lymphocytes. Am J Respir Crit Med,2005;172(3):322-8
60 Freeman JL, Gonzalo P, Pitcher JA, Claing A, Laverque JP, Reboud JP, Lefkowitz RJ. Beta 2-adrenergic receptor stimulated,G protein-coupled receptor kinase 2 mediated,phosphorylation of ribosomal protein P2.Biochemistry,2002;41(42):12850-7
61 Maria Stella Lombardi, Annemieke Kavelaars, Pieter M.Cobelens, Reinhold E.Schmidt, Manfred Schedlowski, Cobi J.Heijnen. Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System. The Journal of Immunology,2001;1635-40
62 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberq RJ, Horne MC, Hoshi T, Hell JW. A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel.Science,2001;293(5527):98-101
63 Carreno BM, Collins M. The B7 family of ligands and its receptor:new pathways for costimulation and inhibition of immune responses.Annu Rev Immunol,2002;20:29-53
64 Elenkov IJ, Chrousos GP. Stress hormones,proinflammatory and antiinflammatory cytokines,and autoimmunity.Ann N Y Acad Sci,2002;966:290-303
65 Joseph R, Podojil, Virginia M.Sanders. CD86 andβ2-adrenergic receptorstimulation regulate B-cell activity cooperatively.TRENDS in Immunology,2005;26(4):180-5
66 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med,2001;344(12):907-16
67 Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science,1993;262(5135):905-7
68 Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Grav GS, Miller J, Bluestone JA. Expression and functional significance of an additional ligand for CTLA-4.Proc Nat Acad Sci U S A,1993;90(23):11054-8
69 Kasprowicz DJ, Kohm AP, Berton MT, Chruscinski AJ, Sharpe A, Sanders VM. Stimulation of the B cell receptor,CD86(B7-2),and the beta 2-adrenergic receptor intrinsically modulates the level of IgG1 produced per B cell.J Immunol,2000;165(2): 680-90
70 David Daikh, David Wofsy, John B. Imbodent.The CD28-B7 costimulatory pathway and its role in autoimmune disease. Journal of Leukocyte Biology,1997;62(8):157-62
1 Johnson M.The beta-adrenoceptor.Am J Respir Crit Care Med,1998;158:s146-s153
2 Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko c, Strosberg AD. Molecular characterization of the humanβ3-adrenergic receptor. Science,1989;245(4922):1118-21
3 Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberq AD. Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization. Proc Natl Acad Sci U S A,1987;84(20): 6995-9
4 Frielle T, Caron MG, Lefkowitz RJ. Properties of the beta 1- and beta 2-adrenergic- receptor subtypes revealed by molecular cloning. Clin Chem,1989;35(5):721-5
5 Mackiewicz U, Klemenska E, Beresewicz A. Beta-adrenergic receptors in normal and failing heart. Kardiol Pol,2007;65(3):294-302
6 Rangel-Lopez A, Pina-Sanchez P, Salcedo M. Genetic variations of the tumor suppressor TP53:outstanding and strategies of analysis. Rev Invest Clin,2006;58(3): 254-64
7 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW. A beta 2-adrenergic receptor signaling complex assembled with the Ca+ channel Cav1.2. Science,2001;293(5527):98-101
8 Takakura Y, Yoshida T. Beta 3-adrenergic receptor agonists-past,present and furture. Nippon Yakurigaku Zasshi,2001;118(5):315-20
9 Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptor. Nat Rev Mol Cell Biol,2002;3(9):639-50
10 Mialet-Perez J, Green SA, Miller WE, Liqqett SB. A primate-dominant third glycosylation site of the beta 2-adrenergic receptor routes receptors to degradation during agonist regulation. J Biol Chem,2004;279(37):38603-7
11 Moffett S, Roussrau G, Lagace M, Bouver M. The palmitoylation state of the beta(2)-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and beta-adrenergic receptor kinase involved in its phosphorylation and desensitization. J Neurochem,2001;76(1):269-79
12 Johnson M. Molecular mechanisms of beta 2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol,2006;117(1):18-24
13 Fraser LR, Adeoya-Osiguwa S. Modulation of adenylyl cyclase by FPP and adenosine involves stimulatory and inhibitory adenosine receptors and g proteins. Mol Reprod Dev,1999;53(4):459-71
14 Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ. The beta 2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange. Nature,1998;392(6676):626-30
15 Robison GA, Butcher RW, Sutherland EW. Adenyl cyclase as an adrenergic receptor. Ann N Y Acad Sci,1967;139(3):703-23
16 Giembycz MA, Newton R. Beyond the dogma: novel beta2-adrenoceptor signalling in the airways. Eur Respair J,2006;27(6):1286-306
17 Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the beta 2-adrenergic receptor to different G proteins by protein kinase A. Nature,1997; 390(6655):88-91
18 Bonacci JV, Stewart AG.. Regulation of human airway mesenchymal cell proliferation by glucocorticoids and beta 2-adrenoceptor agonists.Pulm Pharmacol Ther,2006;19(1):32-8
19 Johnson M. Interactions between corticosteroids and beta2-agonists in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc,2004;1(3):200-6
20 McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies theairway beta-agonist paradox. J Clin Invest,2003;112(4):495-7
21 Sarria B, Naline E, Zhang Y, Cortijo J, Molimard M, Moreau J, Therond P, Advenier C, Morcillo EJ. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol,2002; 283(5):L1125-32
22 McGraw DW, Liggett,SB. Molecular mechanisms of beta 2-adrenergic receptor function and regulation.Proc Am Thorac Soc,2005;2(4):292-6
23 Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ. Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin.Science,2001; 294(5545):1307-13
24 Chorley BN, Li Y, Fang S, Park JA, Adler KB. (R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS. Am J Respir Cell Mol Biol,2006; 34(1):119-27
25 McGraw DW, Liggett SB. Heterogeneity in beta-adrenergic receptor kinase expression in the lung accounts for cell-specific desensitization of the beta 2-adrenergic receptor. J Biol Chem,1997;272(11):7338-44
26 Palmer TM, Stiles GL. Structure-function analysis of inhibitory adenosine receptor regulation. Neuropharmacology,1997;36(9):1141-7
27 Forleo C, Sorrentino S, Guida P, Romito R, De Tommasi E, Iacoviello M, Pitzalis M. Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy. J Cardiovasc Med,2007;8(8):589-95
28 Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry,1994;33(32):9414-9
29 Sandilands AJ, O'Shaughnessy KM. The functional significance of genetic variation within the beta-adrenoceptor. Br J Pharmacol,2005;60(3):235-43
30 Kay LJ, Rostami-Hodjegan A, Suvarna SK, Peachell PT. Influence of beta2-adrenoceptor gene polymorphisms on beta 2-adrenoceptor-mediated responses in human lung mast cells. Br J Pharmacol,2007;152(3):323-31
31 Xie HG, Stein CM, Kim RB, Xiao ZS, He N, Zhou HH, Gainer JV, Brown NJ, Haines JL, Wood AJ. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacoqenetics,1999;9(4):511-6
32 Denoeud F, Kapranov P, Ucla C, Frankish A, Castelo R, Drenkow J, Lagarde J, Alioto T, Manzano C, Chrast J, Dike S, Wyss C, Henrichsen CN, Holroyd N, Dickson MC, Taylor R, Hance Z, Foissac S, Myers RM, Rogers J, Hubbard T, Harrow J, GuigóR, Gingeras TR, Antonarakis SE, Reymond A. Prominent use of distal 5' transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res,2007;17(6):746-59
2 Aqrawal S, Misra R, Aqqarwal A. Autoantibodies in rheumatoid arth ritis:association with severity of disease in established RA. Clin Rheumatol,2007;26(2):201-4
3 Berek C. Do B cells play an important role in the pathogenesis of rheumatoid arthritis? Z Rheumatol,2005;64(6):383-8.
4 Panayi GS. B cells:a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology,2005;44(2):113-7
5 Kohm AP, Sanders VM. Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo.Pharmacol Rev,2001;53(4):487-525
6 Wahle M, Stachetzki U, Krause A, Pierer M, Hantzschel H, Baerwald CG.. Regulation of beta 2-adrenergic receptors on CD4 and CD8 positive lymphocytes by cytokines in vitro.Cytokine,2001;16(6):205-9
7 Baerwald C, Graefe C, Muhl C, Von Wichert P, Krause A. Beta 2-adrenergic receptors on peripheral blood mononuclear cells in patients with rheumatic diseases.Eur J Clin Invest,1992;22(10):42-6
8 Jon D.Levine, Terence J.Coderre, Clyde Helms, Allan I.Basbaum. Beta2-Adrenergic mechanisms in experimental arthritis. Proc.Natl.Acad.Sci.USA,1988;85:4553-6
9 Coderre TJ, Basbaum AI, Dallman MF, Helms C,Levine JD. Epinephrine exacerbates arthritis by an action at presynaptic beta 2-adrenoceptors. Neuroscience,1990;34(2): 521-3
10 Straub RH, Cutolo M. Involvement of the hypothalamic-pituitary-Adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis:viewpoint based on systemic pathogenetic role. Arthritis Rheum,2001;44(3):493-507
11张鸽,吴玉林,沈磊,王玫,吉蕊.湿迪胶囊对大鼠佐剂性关节炎作用机制的研究.中国中药杂志,2007;32(14):1432-5
12钱娴娟,赵文明,胡永秀.口服Ⅱ型胶原蛋白诱导佐剂性关节炎大鼠免疫耐受的研究.中华风湿病学杂志,2002;6(5):331-4
13 Wei W, Xu XM, Shen YX, Ding CH, Zhang AP, Xu XY. Effects of malatonin on peripheral blood lymphocyte proliferation from patients with rheumatoid arthritis and G protein-coupled cAMP signal transduction.Chin Pharmacol Bull,1998;14(6):530-2
14 Chen Q, Wei W. Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis.Int Immunopharmacol,2002;2(10):1443-9
15 Chen Q, Wei W. Effects and mechanisms of glucoside of chaenomeles speciosa on collagen-induced arthritis in rats. Int Immunopharmacol,2003;3(4):593-608
16 Zheng YQ, Wei W.Total glucosides of paeony suppressed adjuvant arthritis in rats and tntervenes cytokine-signaling between different types of synovicytes. Int Immunopharmacol,2005;5(10):1560-73
17丁长海,徐叔云,熊祖应,梅俏,戴琍明,於传斌.免疫性关节炎模型的制备.见:徐叔云,卞如濂,陈修主编.药理实验方法学,第3版,北京:人民卫生出版社,2002:920
18 Gu WZ, Brandwein R. Inhibition of typeⅡcollagen-induced arthritis in rats by triptolide.Int Immunopharmacol,1998;20(8):389-400
19刘辉主编.临床免疫学和免疫检验实验指导(供医学检验专业用),第二版,北京:人民卫生出版社,2003:50-2
20张玲玲,魏伟,严尚学,孙妩弋,岳莉,王华,吴成义,汪倪萍,李常玉.木瓜苷对小鼠胶原性关节炎的预防作用及初步机制,中国药理学通报;2004;20(1):95-100
21 Lopez-Gonzalez MA, Calvo JR, Osuna C. Synergistic action of melatonin and vasoactive intestinal peptide in stimulating cyclic AMP production in human lymphocytes. J Pineal Res,1992;12(4):174-80
22 Scott DL. Prognostic factors in early rheumatoid arthritis. Rheumatology,2000; 39(1):24-9
23 Kessel A, Rosner I, Zuckerman E, Golan TD, Toubi E. Use of antikeratin antibodies to distinguish between rheumatoid arthritis and polyarthritis associated with hepatitis C infection. J Rheumatol,2000;27(3):610-2
24 Saraux A, Berthelot JM, Devauchelle V, Bendaoud B, Chales G, Le Henaff C, Thorel JB, Hoang S, Jousse S, Baron D, Le Goff P, Youinou P. Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. J Rheumatol, 2003;30(12):2535-9
25 Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann, Smolen JS, Steiner G. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis,2005;64(12):1731-6
26 Puga Yung GL, Le TD, Roord S, Prakken B, Albani S. Heat shock protein(HSP) for immunotherapy of rheumatoid arthritis(RA). Inflamm Res,2003;52(11):443-51
27 Durai M, Gupta RS, Moudgil KD. The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis. J Immunol,2004;172(5):2795-802
28 Nguyen TT, Zlacka D, Vavrincova P, Sedlacek P, Hromadnikova I. Detection of antibodies against 60-, 65- and 70-kDa heat shock proteins in paediatric patients with various disorders using Western blotting and ELISA.Clin Chem Lab Med,2006;44(4): 442-9
29 Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St Clair EW, Tedder TF. B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol,2007;179(2):1369-80
30 Kim HR, Kim EY, Cerny J, Moudgil KD. Antibody responses to mycobacterial and self heat shock protein 65 in autoimmune arthritis: epitope specificity and implication in pathogenesis.J Immunol,2006;177(10):6634-41
31 Durai M, Kim HR, Bala KK, Moudgil KD.T cells against the pathogenic and protective epitopes of heat-shock protein 65 are crossreactive and display functionalsimilarity: novel aspect of regulation of autoimmune arthritis. J Rheumatol,2007;34(11): 2134-43.
32 Satpute SR, Soukhareva N, Scott DW, Moudgil KD. Mycobacterial HSP65-IgG -expressing tolerogenic B cells confer protection against adjuvant-induced arthritis in Lewis rats. Arthritis Rheum,2007;56(5):1490-6
33 Homandberg GA. Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Front biosci.1999;4:713-30.
34 Kohm AP, Mozaffarian A, Sanders VM. B cell Receptor- andβ2-adrenergic receptor-induced regulation of B7-2(CD86) expression in B cells.J Immunol, 2002;168(12):6314-22
35 Sanders VM. The role of norepinephrine and beta-2 adrenergic receptor stimulation in the modulation of Th1,Th2 and B lymphocyte function.Adv Exp Med Biol,1998;437:269-78
36 Podojil JR, Kin NW, Sanders VM. CD86 and beta2-adrenergic receptor signaling pathways,respectively,increase Oct-2 and OCA-B Expression and binding to the 3’-IgH enhancer in B cells.J Biol Chem,2004;279(22):23394-404
37 Ader R, Felten D, Cohen N. Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol,1990;30:561-602
38 Besedovsky HO, Del Rey A. Immune-neuro-endocrine interactions:facts and hypotheses.Endocr Rev,1996;17(1):64-102
39 Kohm AP, Sanders VM. Norepinephrine andβ2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev,2001;53(4):487-525
40 Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol,2004;5(6):575-81
41 Kin NW, Sanders VM. It takes nerve to tell T and B cells what to do. J Leukoc Biol,2006;79(6):1093-104
42 Ziemssen T, Kern S. Psychneuroimmunology-cross-talk between the immune and nervous systems. J Neurol,2007;254(2):Ⅱ8-11
43 Baerwald CG, Wahle M, Ulrichs T, Jonas D, von Bierbrauer A, von Wichert P, Burmester GR, Krause A. Reduced catecholamine response of lymphocytes from patients with rheumatoid arthritis. Immunobiology,1999;200(1):77-91
44 Wahle M, K?lker S, Krause A, Burmester GR, Baerwald CG. Impaired catecholaminergic signalling of B lymphocytes in patients with chronic rheumatic diseases. Ann Rheum Dis,2001;60(5):505-10
45 Wahle M, Krause A, Pierer M, Hantzschel H, Baerwald CG. Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions. Ann N Y Acad Sci,2002;966:355-64
46 Felten DL, Ackerman KD, Wiegand SJ, Felten SY. Noradrenergic sympathetic innervation of the spleen:1.Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J Neurosci Res,1987;18(1):28-36
47葛志东,陈敏珠,徐叔云.大鼠脾淋巴细胞β肾上腺素受体的放射配位体测定.中国药理学通报,1991;12(4):340-3
48葛志东,陈敏珠,徐叔云.交感神经对抗体应答的调控.中国药理学通报,1991;7(3): 161-4.
49葛志东,陈敏珠,徐叔云.SRBC致敏对大鼠脾脏淋巴细胞β-受体的影响.中国免疫学杂志,1991;7(6):202-4
50 Lucin KM, Sander VM, Jones TB, Malarkey WB, Popovich PG. Impaired antibodies synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation.Exp Neurol, 2007;207(1): 75-84
51 Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The symphthetic nerve-an integrative interface between two super systems:the brain and the immune system.Pharmacol Rev,2000;52(4):595-638
52 Kohm AP, Sanders VM. Norepinephrine: a messenger from the brain to the immunesystem.Immunol Today,2000;21(11):539-42
53 Kohm AP, Sanders VM. Suppression of antigen-specific Th2 cell-dependent IgM and IgG1 production following norepinephrine depletion in vivo.J Immunol,1999; 162(9):5299-308
54 Sanders VM. Interdisciplinary research:noradrenergic regulation of adaptive immunity.Brain Behav Immun,2006;79(6):1093-104
55 Podojil JR, Sander VM. Selective regulation of mature IgG1 transcription by CD86 and beta 2-adrenergic receptor stimulation.J Immunol,2003;170(10):5143-51
56 Premont RT, Gainetdinov RR. Physiological roles of G protein-coupled receptor kinase and arrestins. Annu Rev Physiol,2007;69:511-34
57 Siehler S. Cell-based assays in GPCR drug discovery. Biotechnol J,2008;3(4):471-83
58 Mizobe T. Cuerrent aspects of research on agrenergic receptor. Masui,2008;57(1): 22-38
59 Oostendorp J, Postma DS, Volders H, Jonquepier H, Kauffman HF, Boezen HM, Meyers DA, Bleecker ER, Nelemans SA, Zaaqsma J, Meurs H. Differential desensitization of homozygous haplotypes of the beta 2-adrenergic receptor in lymphocytes. Am J Respir Crit Med,2005;172(3):322-8
60 Freeman JL, Gonzalo P, Pitcher JA, Claing A, Laverque JP, Reboud JP, Lefkowitz RJ. Beta 2-adrenergic receptor stimulated,G protein-coupled receptor kinase 2 mediated,phosphorylation of ribosomal protein P2.Biochemistry,2002;41(42):12850-7
61 Maria Stella Lombardi, Annemieke Kavelaars, Pieter M.Cobelens, Reinhold E.Schmidt, Manfred Schedlowski, Cobi J.Heijnen. Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System. The Journal of Immunology,2001;1635-40
62 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberq RJ, Horne MC, Hoshi T, Hell JW. A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel.Science,2001;293(5527):98-101
63 Carreno BM, Collins M. The B7 family of ligands and its receptor:new pathways for costimulation and inhibition of immune responses.Annu Rev Immunol,2002;20:29-53
64 Elenkov IJ, Chrousos GP. Stress hormones,proinflammatory and antiinflammatory cytokines,and autoimmunity.Ann N Y Acad Sci,2002;966:290-303
65 Joseph R, Podojil, Virginia M.Sanders. CD86 andβ2-adrenergic receptorstimulation regulate B-cell activity cooperatively.TRENDS in Immunology,2005;26(4):180-5
66 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med,2001;344(12):907-16
67 Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science,1993;262(5135):905-7
68 Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Grav GS, Miller J, Bluestone JA. Expression and functional significance of an additional ligand for CTLA-4.Proc Nat Acad Sci U S A,1993;90(23):11054-8
69 Kasprowicz DJ, Kohm AP, Berton MT, Chruscinski AJ, Sharpe A, Sanders VM. Stimulation of the B cell receptor,CD86(B7-2),and the beta 2-adrenergic receptor intrinsically modulates the level of IgG1 produced per B cell.J Immunol,2000;165(2): 680-90
70 David Daikh, David Wofsy, John B. Imbodent.The CD28-B7 costimulatory pathway and its role in autoimmune disease. Journal of Leukocyte Biology,1997;62(8):157-62
1 Johnson M.The beta-adrenoceptor.Am J Respir Crit Care Med,1998;158:s146-s153
2 Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko c, Strosberg AD. Molecular characterization of the humanβ3-adrenergic receptor. Science,1989;245(4922):1118-21
3 Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberq AD. Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization. Proc Natl Acad Sci U S A,1987;84(20): 6995-9
4 Frielle T, Caron MG, Lefkowitz RJ. Properties of the beta 1- and beta 2-adrenergic- receptor subtypes revealed by molecular cloning. Clin Chem,1989;35(5):721-5
5 Mackiewicz U, Klemenska E, Beresewicz A. Beta-adrenergic receptors in normal and failing heart. Kardiol Pol,2007;65(3):294-302
6 Rangel-Lopez A, Pina-Sanchez P, Salcedo M. Genetic variations of the tumor suppressor TP53:outstanding and strategies of analysis. Rev Invest Clin,2006;58(3): 254-64
7 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A, Weinberg RJ, Horne MC, Hoshi T, Hell JW. A beta 2-adrenergic receptor signaling complex assembled with the Ca+ channel Cav1.2. Science,2001;293(5527):98-101
8 Takakura Y, Yoshida T. Beta 3-adrenergic receptor agonists-past,present and furture. Nippon Yakurigaku Zasshi,2001;118(5):315-20
9 Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptor. Nat Rev Mol Cell Biol,2002;3(9):639-50
10 Mialet-Perez J, Green SA, Miller WE, Liqqett SB. A primate-dominant third glycosylation site of the beta 2-adrenergic receptor routes receptors to degradation during agonist regulation. J Biol Chem,2004;279(37):38603-7
11 Moffett S, Roussrau G, Lagace M, Bouver M. The palmitoylation state of the beta(2)-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and beta-adrenergic receptor kinase involved in its phosphorylation and desensitization. J Neurochem,2001;76(1):269-79
12 Johnson M. Molecular mechanisms of beta 2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol,2006;117(1):18-24
13 Fraser LR, Adeoya-Osiguwa S. Modulation of adenylyl cyclase by FPP and adenosine involves stimulatory and inhibitory adenosine receptors and g proteins. Mol Reprod Dev,1999;53(4):459-71
14 Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ. The beta 2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange. Nature,1998;392(6676):626-30
15 Robison GA, Butcher RW, Sutherland EW. Adenyl cyclase as an adrenergic receptor. Ann N Y Acad Sci,1967;139(3):703-23
16 Giembycz MA, Newton R. Beyond the dogma: novel beta2-adrenoceptor signalling in the airways. Eur Respair J,2006;27(6):1286-306
17 Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the beta 2-adrenergic receptor to different G proteins by protein kinase A. Nature,1997; 390(6655):88-91
18 Bonacci JV, Stewart AG.. Regulation of human airway mesenchymal cell proliferation by glucocorticoids and beta 2-adrenoceptor agonists.Pulm Pharmacol Ther,2006;19(1):32-8
19 Johnson M. Interactions between corticosteroids and beta2-agonists in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc,2004;1(3):200-6
20 McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies theairway beta-agonist paradox. J Clin Invest,2003;112(4):495-7
21 Sarria B, Naline E, Zhang Y, Cortijo J, Molimard M, Moreau J, Therond P, Advenier C, Morcillo EJ. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol,2002; 283(5):L1125-32
22 McGraw DW, Liggett,SB. Molecular mechanisms of beta 2-adrenergic receptor function and regulation.Proc Am Thorac Soc,2005;2(4):292-6
23 Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ. Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin.Science,2001; 294(5545):1307-13
24 Chorley BN, Li Y, Fang S, Park JA, Adler KB. (R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS. Am J Respir Cell Mol Biol,2006; 34(1):119-27
25 McGraw DW, Liggett SB. Heterogeneity in beta-adrenergic receptor kinase expression in the lung accounts for cell-specific desensitization of the beta 2-adrenergic receptor. J Biol Chem,1997;272(11):7338-44
26 Palmer TM, Stiles GL. Structure-function analysis of inhibitory adenosine receptor regulation. Neuropharmacology,1997;36(9):1141-7
27 Forleo C, Sorrentino S, Guida P, Romito R, De Tommasi E, Iacoviello M, Pitzalis M. Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy. J Cardiovasc Med,2007;8(8):589-95
28 Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry,1994;33(32):9414-9
29 Sandilands AJ, O'Shaughnessy KM. The functional significance of genetic variation within the beta-adrenoceptor. Br J Pharmacol,2005;60(3):235-43
30 Kay LJ, Rostami-Hodjegan A, Suvarna SK, Peachell PT. Influence of beta2-adrenoceptor gene polymorphisms on beta 2-adrenoceptor-mediated responses in human lung mast cells. Br J Pharmacol,2007;152(3):323-31
31 Xie HG, Stein CM, Kim RB, Xiao ZS, He N, Zhou HH, Gainer JV, Brown NJ, Haines JL, Wood AJ. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacoqenetics,1999;9(4):511-6
32 Denoeud F, Kapranov P, Ucla C, Frankish A, Castelo R, Drenkow J, Lagarde J, Alioto T, Manzano C, Chrast J, Dike S, Wyss C, Henrichsen CN, Holroyd N, Dickson MC, Taylor R, Hance Z, Foissac S, Myers RM, Rogers J, Hubbard T, Harrow J, GuigóR, Gingeras TR, Antonarakis SE, Reymond A. Prominent use of distal 5' transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res,2007;17(6):746-59
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |