类风湿关节炎、强直性脊柱炎和骨关节炎滑膜成纤维样细胞增殖与分化的体外研究
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摘要
目的 类风湿关节炎(rheumatoid arthritis,RA)是主要表现为周围对称性多关节慢性炎症的自身免疫性疾病。类风湿关节炎的基本病理变化为滑膜炎。滑膜成纤维样细胞(FLS)过度增生，大量T淋巴细胞和巨噬细胞浸润，以及血管翳的形成。异常增生的FLS分泌基质蛋白酶和致炎性细胞因子，促发炎症和免疫反应，是导致软骨和骨质的破坏的主要因素。抑制FLS的异常增殖或诱导FLS分化成熟是治疗RA的重要策略。
沙利度胺(Thalidomide)是TNF-α抑制剂和血管生成抑制剂，具有较强的抗炎作用，近年已作为免疫调节剂应用于RA等风湿性疾病。白芍总苷(total glucosides of peony,TGP)是从中国传统的中草药白芍根部中提取的有效成分，具有机能和剂量依赖性的免疫调节作用。基础和临床研究证实，沙利度胺和TGP对类风湿关节炎有一定疗效，改善临床症状。艾拉莫德(Iguratimod,T-614)为一种甲磺酰胺基非甾体类抗炎药(NSAIDs)，是COX-2选择性抑制剂，国外研究表明其对RA患者有一定免疫抑制作用。全反式维甲酸(ATRA)、1，25(OH)_2D_3、地塞米松是已知的细胞分化诱导剂，可促进成纤维细胞的分化成熟，抑制其无限增殖特性，被广泛用于治疗皮肤、肝脏、肺脏纤维化，降低纤维组织增生，但它们对RA的滑膜成纤维细胞增殖影响却鲜有报道。本试验旨在观察RA滑膜FLS的生长特点，研究沙利度胺、TGP、T-614，ATRA、1，25(OH)_2D_3、和地塞米松在体外实验中对RA-FLS细胞增殖分化特性的影响，将更全面地揭示RA的发病机制，探讨免疫调节药物的不同作用方式，验证其临床疗效，寻找治疗RA新途径。
方法 1．组织来源：滑膜组织关节镜诊断治疗术、关节活检针抽取滑膜组织和抽取关节积液培养。收集膝OA(8例)和RA(5例)，RA和OA患者的诊断均
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease that mainly affects multiple synovial joints. Synovitis may be present in RA. Inflammation is accompanied by an influx of immune competent cells and by aberrant proliferation of resident fibroblast-like synovial cells (FLS) . Accretion of FLS is responsible for progressive joint destruction.
T-614 [N-(3-formylamino- 4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide] is known as cyclooxygenase-2(COX-2) inhibitor and total glucosides of paeony (TGP) are active compounds extracted from the roots of Paeonia lactiflora Pall, both are efficient in anti-inflammation and immunoregulation in arthritis via various pathways. The tumor necrosis factor-alpha (TNF-α) inhibitor thalidomide is known to be a potential modulator of host immunity, a potential treatment for autoimmune disorders such as rheumatoid arthritis (RA).
All trans retinoid acid (ATRA) , 1,25 (OH)_2D_3 and desamethasone are known as inducer for cell differentiation and inhibitor to fibroblast cells proliferatiation. The effect on FLS proliferatiation and apoptosis is still unclear.
In this study, we investigate the proliferation characteristics of FLS in RA and OA patients in vitro and the mechanism of the immunosuppressive effect of thalidomide, TGP , T-614, ATRA, 1,25 (OH)_2D_3 and desamethasone on them.
沙利度胺(Thalidomide)是TNF-α抑制剂和血管生成抑制剂，具有较强的抗炎作用，近年已作为免疫调节剂应用于RA等风湿性疾病。白芍总苷(total glucosides of peony,TGP)是从中国传统的中草药白芍根部中提取的有效成分，具有机能和剂量依赖性的免疫调节作用。基础和临床研究证实，沙利度胺和TGP对类风湿关节炎有一定疗效，改善临床症状。艾拉莫德(Iguratimod,T-614)为一种甲磺酰胺基非甾体类抗炎药(NSAIDs)，是COX-2选择性抑制剂，国外研究表明其对RA患者有一定免疫抑制作用。全反式维甲酸(ATRA)、1，25(OH)_2D_3、地塞米松是已知的细胞分化诱导剂，可促进成纤维细胞的分化成熟，抑制其无限增殖特性，被广泛用于治疗皮肤、肝脏、肺脏纤维化，降低纤维组织增生，但它们对RA的滑膜成纤维细胞增殖影响却鲜有报道。本试验旨在观察RA滑膜FLS的生长特点，研究沙利度胺、TGP、T-614，ATRA、1，25(OH)_2D_3、和地塞米松在体外实验中对RA-FLS细胞增殖分化特性的影响，将更全面地揭示RA的发病机制，探讨免疫调节药物的不同作用方式，验证其临床疗效，寻找治疗RA新途径。
方法 1．组织来源：滑膜组织关节镜诊断治疗术、关节活检针抽取滑膜组织和抽取关节积液培养。收集膝OA(8例)和RA(5例)，RA和OA患者的诊断均
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease that mainly affects multiple synovial joints. Synovitis may be present in RA. Inflammation is accompanied by an influx of immune competent cells and by aberrant proliferation of resident fibroblast-like synovial cells (FLS) . Accretion of FLS is responsible for progressive joint destruction.
T-614 [N-(3-formylamino- 4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide] is known as cyclooxygenase-2(COX-2) inhibitor and total glucosides of paeony (TGP) are active compounds extracted from the roots of Paeonia lactiflora Pall, both are efficient in anti-inflammation and immunoregulation in arthritis via various pathways. The tumor necrosis factor-alpha (TNF-α) inhibitor thalidomide is known to be a potential modulator of host immunity, a potential treatment for autoimmune disorders such as rheumatoid arthritis (RA).
All trans retinoid acid (ATRA) , 1,25 (OH)_2D_3 and desamethasone are known as inducer for cell differentiation and inhibitor to fibroblast cells proliferatiation. The effect on FLS proliferatiation and apoptosis is still unclear.
In this study, we investigate the proliferation characteristics of FLS in RA and OA patients in vitro and the mechanism of the immunosuppressive effect of thalidomide, TGP , T-614, ATRA, 1,25 (OH)_2D_3 and desamethasone on them.
引文
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3. Tanaka K, Kawasaki H, Kurata K,et al.T-614, a novel antirheumatic drug, inhibits both the activity and induction of cyclooxygenase-2(COX-2) in cultured fibroblasts. Jpn J Pharmacol, 1995, 67: 305-14.
4. Tanaka K, Shimotori T, Taniguchi Y, et al. Pharmacological studies on T-614, a novel antiinflammatory agent: effect on type Ⅱ collagen-induced arthritis in DBA/1J mice and spontaneous arthritis in MRL/1 mice. Int J Immunotherapy, 1993,9:69-78.
5. Inaba T, Tanaka K, Takeno R, et al. Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models. Chem Pharm Bull(Tokyo), 2000, 48: 131-39.
6．王斌，姚余有等．白芍总苷对AA大鼠关节损伤的保护作用．中国药理学与毒理学杂志，1996，10：211-14．
7. Zhu L, Wei W, Zheng YQ. Effects and mechanisms of total glucosides of paeony on joint damage in rat collagen-induced arthritis. Inflamm Res,2005, 54: 211-20.
8. Jayne A. Keifer, Denis C. et al.Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity . J Biol Chem, 2001, 276:22382-87.
9. Bombini G, Canetti C, Rocha FA, et. al. Tumour necrosis factor-alpha mediates neutrophil migration to the knee synovial cavity during immune inflammation. Eur J Pharmacol, 2004, 496: 197-204.
10. Lainer DT, Brahn E. New anti angiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs, 2005, 14: 1-17.
11. Tsuzaki M, Guyton G, Garrett W, et al. IL-1 beta induces C0X2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res, 2003, 21: 256-64.
12. Liebermann DA, Gregory B, Hoffman B. AP-1 (Fos/Jun) transcription factors in hematopoietic differentiation and apoptosis. Int J Oncol, 1998, 12:685-700.
13. Baeten D, Peene I, Union A, et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum , 2001, 44:2255-62.
14. Dowthwaite GP, Edwards JCW, Pitsillides AA. An essential role for the interaction between hyaluronan and hyaluronan binding proteins during joint development. J Histochem Cytochem ,1998, 46:641-51.
15. Baeten D, Kruithof E, Rycke LD, et al. Infiltration of the synovial membrane with macrophage subsets and polymorphonuclear cells reflects global disease activity in spondyloarthropathy. Arthritis Res Ther, 2005, 7:359-69.
16. Baeten D, Demetter P, Cuvelier CA, et al. Macrophages expressing the scavenger receptor 163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol , 2002, 196:343-50.
17. Dorenbosch HL, Tubergen A, Spoorenberg A, et al. The influence of peripheral arthritis on disease activity in ankylosing spondylitis patients as measured with the Bath Ankylosing Spndylitis Activity Index. Arthritis Rheum, 2004, 51:154-59.
18. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther, 2005, 7: 569-80.
19. Baeten D, Kruithof E, Bosch DF, et al. Immunomodulatory effects of anti-tumor necrosis factor a therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study. Arthritis Rheum, 2001, 44:186-195.
20. Evangelisto A, Wakefield R, Emery P. Imaging in early arthritis. Best Pract Res Clin Rheumatol, 2004,18:927-43.
21. Baeten D, Demetter P, Cuvelier C, et al. Comparative study of synovial histology in rheumatoid arthritis, spondyloarthropathy and osteoarthritis: influence of disease duration and activity. Ann Rheum Dis, 2000, 59:945-53.
22. Kraan MK, Haringman JJ, Post WJ, et al. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology, 1999, 38: 1074-80.
23. Youssef PP, Kraan MC, Breedveld FC et al. Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy. Arthritis Rheum ,1998, 41:663-69.
24. Tak PP, Lindblad S, Klareskog L, et al. Synovial biopsies for analysis of the synovial membrane: new perspectives. Newsl Eur Rheumatol Res, 1994,2:27-29.
25. Bresnihan B. Diagnostic value of synovial biopsies. Ann Rheum Dis, 2005, 64: 94.
26. Amos N, Lauder S, Evans A, et al. Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IκBα reveals that most, but not all, inflammatory and destructive mediators are NFκB dependent. Rheumatology, 2006, 10: 1093-78.
27. AikawaY, Yamamoto M, Yamamoto T, et al. An anti-rheumatic agent T-614 inhibits NF-kappaB activation in LPS- and TNF-alpha-stimulated THP-1 cells without interfering with IkappaBalpha degradation. Inflamm Res, 2002, 51: 188-94.
28. Riendeau D, Charleson S, Cromlish W, et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol, 1997, 75: 1088-95.
29. Tanaka K, Yamamoto T, Aikawa Y, et al. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice.Rheumatology(Oxford),2003,42: 1365-71.
30. Aikawa Y, Tanuma N, Shin T, et, al. A new anti-rheumatic drug, T-614,effectively suppresses the development of autoimmune encephalomyelitis.J Neuroimmunol, 1998, 89: 35-42.
31. Kawakami A, Tsuboi M, Urayama S, et al. Inhibitory effect of a new anti-rheumatic drug T-614 on costimulatory molecule expression, cytokine production, and antigen presentation by synovial cells. J Lab Clin Med,1999, 133: 566-74.
32．王兴旺，陈敏珠，徐叔云．白芍总苷对T淋巴细胞亚群的作用。中国药理学通报，1992，8：340-44．
33．李俊，梁俊山，周爱武．白芍总苷对B淋巴细胞增殖和白介素1生成的调节作用．中国药理学与毒理学杂志，1994，8：53-55．
34．王斌，陈敏珠，徐叔云．白芍总苷对大鼠腹腔巨噬细胞产生肿瘤坏死因子的调节机制．中国药理学通报，1997，13：255-57．
35．王志坚、万军梅、陈敏珠 白芍总苷对正常人与类风湿关节炎患者单核细胞和淋巴细胞功能的影响 中国药理学通报，1994；10；197-201．
36．李俊、陈敏珠、徐叔云 白芍总苷对大鼠腹腔巨噬细胞产生前列腺素E_2的作用及部分作用机制的研究 中国药理学通报 1994，18：43．
37．李俊、赵维中、陈敏珠、白芍总苷对大鼠腹腔巨噬细胞产生白三烯B4的影响。中国药理学通报 1992，10：267-70．
38．栗占国．风湿病的免疫及生物治疗进展．中国新药杂志，2001，10：488．
39．王斌、姚余有、周爱武等 白芍总苷对佐剂性关节炎大鼠的免疫调节作用及其与一氧化氮的关系 中国免疫学杂志 1996，12：104-06．
40．王斌、陈敏珠、徐叔云 白芍总苷对佐剂性关节炎大鼠滑膜细胞功能和脾细胞增殖反应的影响 中国药理学与毒理学杂志，1994，8：129-31．
41. Capitosti SM, Hansen TP, Brown ML. Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer. Bioorg Med Chem,2004, 12: 327-36.
42. Gockel HR, Lugering A, Heidemann J, et al. Thalidomide Induces Apoptosis in Human Monocytes by Using a Cytochrome c-Dependent Pathway. The Journal of Immunology, 2004, 172: 5103-09.
43. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet, 2004, 363(9423):1802-11.
44. Kobayashi JH, Yagyu T, Kondo T, et al. Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor κB Activation and Subsequently Suppressed Ovarian Cancer Dissemination. Cancer Res, 2005, 65: 10464-71.
45. Yasui K, Kobayashi N, Yamazaki T, et al. Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des, 2005, 11: 395-401.
46. Jayne A. Keifer, Denis C. et al. Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity-J. Biol. Chem., 2001, 276:22382-87.
47. Mary A, Lokuta, Anna Huttenlocher. TNF-α promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway. Journal of Leukocyte Biology. 2005, 78:210-19.
48. Wary KK , Humtsoe JO. Anti-lipid phosphate phosphohydrolase-3 (LPP3) antibody inhibits bFGF- and VEGF-induced capillary morphogenesis of endothelial cells. Cell Commun Signal, 2005,3: 9.
49. Lainer DT , Brahn E. New antiangiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs, 2005, 14: 1-17.
50. Gnant MF, Turner EM , Alexander HR . Effects of hyperthermia and tumour necrosis factor on inflammatory cytokine secretion and procoagulant activity in endothelial cells. Cytokine, 2000, 12: 339-47.
51. Friedl J, Puhlmann M, David L. et al. Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF. Blood, 2002, 100: 1334-39.
52. Fujita J, Mestre JR, Jerome B. et al. Thalidomide and Its Analogues Inhibit Lipopolysaccharide-mediated Induction of Cyclooxygenase-2. Clin. Cancer Res, 2001, 7: 3349.
53. Mestre JR, Mackrell PJ, Rivadeneira DE, et al. Redundancy in the Signaling Pathways and Promoter Elements Regulating Cyclooxygenase-2 Gene Expression in Endotoxin-treated Macrophage/Monocytic Cells. J Biol Chem, 2001, 276: 3977-82.
54. Payvandi P, Wu L, Haley M, et al. Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol, 2004,230: 81-88.
55. Noguchi T, Shimazawa R, Nagasawa K, et al. Thalidomide and its analogues as cyclooxygenase inhibitors. Bioorg Med Chem Lett, 2002, 12: 1043-46.
56. Culo MI, Vergles D, Horvat G, et al. The levels of TNF-alpha, CAMP, PGE2 and IL-18 in synovial fluid of patients with rheumatoid arthritis and in patients with osteoarthritis. Ann Rheum Dis, 2005, 64: 1831.
57. Sumariwalla PF, Cao Y, Wu HL, et al. The angiogenesis inhibitor protease-activated kringles 1-5 reduces the severity of murine collagen-induced arthritis. Arthritis Res Ther, 2003, 5: 32-39.
58. Clavel G, Bessis N, Boissier MC. Recent data on the role for angiogenesis in rheumatoid arthritis. Joint Bone Spine, 2003, 70: 321-6.
59. Lainer DT, Brahn. E. New anti angiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs, 2005, 14: 1-17.
60. Davis JCJ, Huang F, Maksymowych W. New therapies for ankylosing spondylitis: etanercept, thalidomide, and pamidronate. Rheum Dis Clin North Am, 2003, 29: 481-94.
61. Wei JC, Chan TW, Lin HS, et al. Thalidomide for severe refractory ankylosing spondylitis: a 6-month open-label trial. J Rheumatol, 2003, 30: 2627-31.
62. Toussirot E, Wendling D. Therapeutic advances in ankylosing spondylitis. Expert Opin Investig Drugs, 2001, 10: 21-29.
1. Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis: passive responder or transformed aggressors? Arthritis Rheum, 1996, 223:117-26.
2. Kramer I, Wibulswas A, Croft D, et al. Rheumatoid arthritis: targeting the proliferative fibroblast. Prog Cell Res, 2003, 5:59-70.
3. Spector TD, Hart DJ, Nandra D et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum, 1997, 40: 723-27.
4. Haywood L, McWilliams DF, Pearson CI, et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum, 2003, 48(8):2173-77.
5. Rhodes L A, Grainger A J, Keenan A M. et al. The validation of simple scoring methods for evaluating compartment-specific synovitis detected by MRI in knee osteoarthritis. Rheumatology, 2005, 44 (12) : 1569-73.
6. Middleton J, Manthey A, Tyler J. Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage. J Histochem Cytochem, 1996,44:133-41. 7. Tanaka K, Kawasaki H, Kurata K , et al.T-614, a novel antirheumatic drug, inhibits both the activity and induction of cyclooxygenase-2 (COX-2) in cultured fibroblasts. Jpn J Pharmacol, 1995, 67(4): 305-14.
8. Tanaka K, Shimotori T, Taniguchi Y, et al. Pharmacological studies on T-614, a novel antiinflammatory agent:effect on type Ⅱ collagen-induced arthritis in DBA/1J mice and spontaneous arthritis in MRL/1 mice. Int J Immunotherapy, 1992,9:69-78.
9. Inaba T, Tanaka K, Takeno R, et al. Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6 -phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models. Chem Pharm Bull (Tokyo), 2000, 48(1): 131-39.
10．王斌，姚余有等．白芍总苷对AA大鼠关节损伤的保护作用．中国药理学与毒理学杂志，1996，10(3)：211-14．
11. Zhu L, Wei W, Zheng YQ. Effects and mechanisms of total glucosides of paeony on joint damage in rat collagen-induced arthritis. Inflamm Res, 2005, 54(5): 211-20.
12. Jayne A. Keifer, Denis C. et al. Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity. J Biol Chem, 2001, 276(25):22382-87.
13. Bombini G, Canetti C, Rocha FA, et. al. Tumour necrosis factor-alpha mediates neutrophil migration to the knee synovial cavity during immune inflammation. Eur J Pharmacol, 2004, 496(8): 197-204.
14. Lainer DT, Brahn E. New anti angiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs, 2005, 14(1): 1-17.
15. Tsuzaki M, Guyton G, Garrett W, et al. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res, 2003, 21(2): 256-64.
16. Liebermann DA, Gregory B, Hoffman B. AP-1 (Fos/Jun) transcription factors in hematopoietic differentiation and apoptosis. Int J Oncol, 1998, 12(3): 685-700.
17. Evangelisto A, Wakefield R, Emery P. Imaging in early arthritis. Best Pract Res Clin Rheumatol, 2004, 18(6):927-43.
18. Baeten D, Demetter P, Cuvelier C, et al. Comparative study of synovial histology in rheumatoid arthritis, spondyloarthropathy and osteoarthritis: influence of disease duration and activity. Ann Rheum Dis, 2000, 59:945-53.
19. Kraan MK, Haringman JJ, Post WJ, et al. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology, 1999, 38: 1074-80.
20. Youssef PP, Kraan MC, Breedveld FC et al. Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy. Arthritis Rheum , 1998,41:663-69.
21. Tak PP, Lindblad S, Klareskog L, et al. Synovial biopsies for analysis of the synovial membrane: new perspectives. Newsl Eur Rheumatol Res, 1994,2:27-29.
22. Bresnihan B. Diagnostic value of synovial biopsies. Ann Rheum Dis, 2005, 64: 94.
23 . Lizzio MM, Salli S, Gremese E, et al. Functional indexes in osteoarthritis of the knee are significantly determined by the presence or not of synovitis .Ann Rheum Dis, 2005, 64: 293.
24. Amos N, Lauder S, Evans A, et al. Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IκBα reveals that most, but not all, inflammatory and destructive mediators are NFκB dependent. Rheumatology, 2006, 10: 1093-78.
25. Mastbergen S.C, Bijlsma JWJ, Lafeber FJPG. Nly IL-1beta/TNF-alpha treated human articular cartilage is sensitive to Prostaglandin E2. Ann Rheum Dis, 2005,64: 475.
26. Siegle I, Klein T, Backman JT, et al. Expression of cyclooxygenase 1 and cyclooxygenase 2 in human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory joint diseases. Arthritis Rheum. 1998 Jan, 41(1): 122-29.
27. FioritoS, Magrini L, Adrey J, et al. Inflammatory status and cartilage regenerative potential of synovial fibroblasts from patients with osteoarthritis and chondropathy. Rheumatology (Oxford) , 2005, 44(2): 164-71.
28. BenitoMJ, VealeDJ, FitzGeraldO, et al. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dise, 2005,64 (9) :1263-67.
29. Lories R J U, Derese I, Bari C De, et al. In vitro growth rate of fibroblast-like synovial cells is reduced by methotrexate treatment. Ann Rheum Dise, 2003, 62 (6) :568-71.
30. Riendeau D, Charleson S, Cromlish W, et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol, 1997, 75(9): 1088-95.
31. AikawaY, Yamamoto M, Yamamoto T, et al. An anti-rheumatic agent T-614 inhibits NF-kappaB activation in LPS- and TNF-alpha-stimulated THP-1 cells without interfering with IkappaBalpha degradation. Inflamm Res, 2002, 51(4): 188-94.
32. Tanaka K, Yamamoto T, Aikawa Y, et al. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology( Oxford) , 2003,42 (11): 1365-71.
33. Aikawa Y, Tanuma N, Shin T, et, al. A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis. J Neuroimmunol, 1998, 89(8): 35-42.
34. Kawakami A, Tsuboi M, Urayama S, et al. Inhibitory effect of a new anti-rheumatic drug T-614 on costimulatory molecule expression, cytokine production, and antigen presentation by synovial cells. J Lab Clin Med, 1999, 133 (6): 566-74.
35. Inaba T, Tanaka K, Takeno R, et al. Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models. Chem Pharm Bull (Tokyo), 2000, 48(1): 131-39.
36. Kohno M, Aikawa Y, Tsubouchi Y, et al. Inhibitory effect of T-614 on tumor necrosis factor-alpha induced cytokine production and nuclear factor-kappaB activation in cultured human synovial cells. J Rheumatol, 2001, 28(12): 2591-96.
37．王兴旺，陈敏珠，徐叔云．白芍总苷对T淋巴细胞亚群的作用。中国药理学通报，1992，8(5)：340-44．
38．李俊，梁俊山，周爱武．白芍总苷对B淋巴细胞增殖和白介素1生成的调节作用．中国药理学与毒理学杂志，1994，8(1)：53-55．
39．王斌，陈敏珠，徐叔云．白芍总苷对大鼠腹腔巨噬细胞产生肿瘤坏死因子的调节机制．中国药理学通报，1997，13(3)：255-57．
40．王志坚、万军梅、陈敏珠 白芍总苷对正常人与类风湿关节炎患者单核细胞和淋巴细胞功能的影响 中国药理学通报，1994；10(3)：197-201．
41．李俊、陈敏珠、徐叔云 白芍总苷对大鼠腹腔巨噬细胞产生前列腺素E_2的作用及部分作用机制的研究 中国药理学通报 1994，18：43．
42．李俊、赵维中、陈敏珠、白芍总苷对大鼠腹腔巨噬细胞产生白三烯B4的影响。中国药理学通报 1992，10：267-70．
43．栗占国．风湿病的免疫及生物治疗进展．中国新药杂志，2001，10(7)：488．
44．王斌、姚余有、周爱武等 白芍总苷对佐剂性关节炎大鼠的免疫调节作用及其与一氧化氮的关系 中国免疫学杂志 1996，12(2)：104-06．
45．王斌、陈敏珠、徐叔云 白芍总苷对佐剂性关节炎大鼠滑膜细胞功能和脾细胞增殖反应的影响 中国药理学与毒理学杂志，1994，8(2)：129-31．
46．王志坚，陈敏珠，孙桂华等 白芍总苷治疗类风湿关节炎的临床药理研究。中国药理学通报，1994；10(2)；117-21．
47. Zheng YQ, Wei W. Total glucosides of paeony suppresses adjuvant arthritis in rats and intervenes cytokine-signaling between different types of synoviocytes. It Immunopharmacol, 2005; 5(10): 1560-73.
48. Capitosti SM, Hansen TP, Brown ML. Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer. Bioorg Med Chem, 2004, 12(2): 327-36.
49. Gockel HR, Lugering A, Heidemann J, et al. Thalidomide Induces Apoptosis in Human Monocytes by Using a Cytochrome c-Dependent Pathway. The Journal of Immunology, 2004, 172: 5103-09.
50. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet, 2004, 363(9423):1802-11.
51. Kobayashi JH, Yagyu T, Kondo T, et al. Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor κB Activation and Subsequently Suppressed Ovarian Cancer Dissemination. Cancer Res, 2005, 65: 10464-71.
52. Yasui K, Kobayashi N, Yamazaki T, et al. Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des, 2005, 11(3): 395-401.
53. Jayne A. Keifer, Denis C. et al . Inhibition of NF-κB Activity by Thalidomide through Suppression of 1KB Kinase Activity -J. Biol. Chem., 2001, 276(25): 22382-87.
54. Mary A, Lokuta, Anna Huttenlocher. TNF-α promotes a stop signal that inhibits neutrophil polarization and migration via a p38 MAPK pathway. Journal of Leukocyte Biology. 2005, 78:210-19.
55. Wary KK , Humtsoe JO. Anti-lipid phosphate phosphohydrolase-3 (LPP3) antibody inhibits bFGF- and VEGF-induced capillary morphogenesis of endothelial cells. Cell Commun Signal, 2005,3: 9.
56. Lainer DT , Brahn E. New antiangiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs, 2005, 14(1): 1-17.
57. Gnant MF, Turner EM , Alexander HR . Effects of hyperthermia and tumour necrosis factor on inflammatory cytokine secretion and procoagulant activity in endothelial cells. Cytokine, 2000, 12(4): 339-47.
58. Friedl J, Puhlmann M, David L. et al. Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF. Blood, 2002, 100: 1334-39.
59. Fujita J, Mestre JR, Jerome B. et al. Thalidomide and Its Analogues Inhibit Lipopolysaccharide-mediated Induction of Cyclooxygenase-2. Clin. Cancer Res, 2001, 7: 3349.
60. Mestre JR, Mackrell PJ, Rivadeneira DE, et al. Redundancy in the Signaling Pathways and Promoter Elements Regulating Cyclooxygenase-2 Gene Expression in Endotoxin-treated Macrophage/Monocytic Cells. J Biol Chem, 2001, 276: 3977-82.
61. Payvandi P, Wu L, Haley M, et al. Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-lbeta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol, 2004,230(2): 81-88.
62. Noguchi T, Shimazawa R, Nagasawa K, et al. Thalidomide and its analogues as cyclooxygenase inhibitors. Bioorg Med Chem Lett, 2002, 12(7): 1043-46.
63. Culo MI, Vergles D, Horvat G, et al. The levels of TNF-alpha, CAMP, PGE2 and IL-18 in synovial fluid of patients with rheumatoid arthritis and in patients with osteoarthritis. Ann Rheum Dis, 2005, 64: 1831.
64. Sumariwalla PF, Cao Y, Wu HL, et al.The angiogenesis inhibitor protease-activated kringles 1-5 reduces the severity of murine collagen-induced arthritis. Arthritis Res Ther, 2003, 5(1): 32-39.
64. Clavel G, Bessis N, Boissier MC. Recent data on the role for angiogenesis in rheumatoid arthritis. Joint Bone Spine, 2003, 70(5): 321-6.
66. Scott BB, Zaratin PF, Gilmartin AG, et al. TNF-alpha modulates angiopoietin-1 expression in rheumatoid synovial fibroblasts via the NF-kappa B signalling pathway. Biochem Biophys Res Commun, 2005, 328(2): 409-14.
67. Nagashima M, Tanaka H, Takahashi H, et al. Study of the mechanism involved in angiogenesis and synovial cell proliferation in human synovial tissues of patients with rheumatoid arthritis using SCID mice. Lab Invest, 2002, 82(8): 981-88.
68. Oliver SJ, Freeman SL, Corral LG, et al. Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis. Clin Exp Immunol, 1999, 118(2): 315-21.
69. Bombini G, Canetti C, Rocha FA, et al. Tumour necrosis factor-alpha mediates neutrophil migration to the knee synovial cavity during immune inflammation. Eur J Pharmacol, August 2, 2004, 496(1-3): 197-204.
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