大鼠佐剂性关节炎滑膜细胞G蛋白偶联信号通路与MAPK信号通路的关系及白芍总苷的作用
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摘要
类风湿关节炎(rheumatoid arthritis,RA)是一种以关节滑膜炎症为主要病理表现的慢性、系统性和破坏性的自身免疫性关节疾病,全世界患病率约1～1.5%。其病理特点为关节滑膜在多种炎性因子的刺激下呈类肿瘤样无限增生、新血管形成、关节囊增厚,增生的滑膜表面形成血管翳,并最终破坏关节软骨和软骨下骨,使关节畸形和失去功能。关节炎治疗的首要目的是控制炎症、阻止关节破坏。由于RA的发病机制尚不清楚,目前还没有令人满意的疗法。运用分离提纯和化学结构测定新技术分离的天然药物有效部位在RA的治疗中得到广泛运用,其中白芍总苷(total glucosides of paeony,TGP)是从传统中药亳白芍(paeonia lactiflora Pall)干燥根中提取的有效部位,主要成分为芍药苷等,已被批准生产上市,临床上长期使用,治疗RA疗效较显著,不良反应小。但是作为大分子的中药有效部位如何作用于RA滑膜细胞、并进一步影响胞内的信号转导途径,从而调节炎症介质分泌或功能蛋白表达失衡,目前尚不清楚。鸟苷酸结合蛋白(Guanine nucleotide-binding proteins,G-protein),简称G蛋白,其介导的信号转导通路在炎症免疫性疾病中发挥重要作用。细胞因子、神经递质、激素、磷脂、光刺激、嗅觉及味觉特异性配基和丝裂原均可通过跨膜的G蛋白偶联受体(G-protein-coupled receptors,GPCRs)引发G蛋白活化及其下游信号传递。而白细胞介素-1(interleukin-1,IL-1)是在RA软骨降解和骨破坏中起主要作用的细胞因子之一,可引起RA滑膜细胞胶原酶合成、前列腺素类(prostaglandins,PGs)释放和胞内丝裂原激活的蛋白激酶(mitogen-activated protein kinases,MAPK)通路的活化。本研究采用大鼠佐剂性关节炎(adjuvant arthritis,AA)模型,深入研究滑膜细胞中IL-1介导的MAPK通路的活化与G
Rheumatoid arthritis (RA) is one of the most serious medical problems affecting approximately 1 ~ 1.5 % of all people worldwide. A major obstacle to the development of rational treatment strategies is that the disease mechanisms remain largely unknown and clues may come from experimental arthritis. The disease is autoimmune in nature and characterized by chronic inflammation of the synovial tissues in multiple joints that leads to joint destruction. Although palliative treatments are widely prescribed, there are currently only a few treatments that can modify the progression of the disease.Total glucosides of paeony (TGP) is an active compound extracted from roots of paeonia lactiflora Pall which have been recognized as the valuable traditional herbs used in treatment for rheumatoid arthritis (RA) and hepatitis with a long history in traditional Chinese medicine. TGP contains more than 40% percentage of paeoniflorin and other components such as hydroxy-paeoniflorin, paeonin, albiflorin, benzoylpaeoniflorin, et al. It has anti-inflammatory and immune-regulatory effects and has been approved by State Food and Drug Administration (SFDA) for the treatment of RA as a disease-modifying drug.Signaling through stress- and mitogen-activated protein kinases (SAPK/MAPK) pathways in FLS is a typical feature of chronic synovitis in RA. As well known, various MAPK cascades can be activated by guanine nucleotide binding regulatory proteins (G proteins)-coupled receptors (GPCRs)/G-protein components. Thus, the
cytokine-signaling including G protein transmembrane signal and MAPKs pathway became new targets for treatment of RA. Interleukin-1 (IL-1) is an important pro-inflammation cytokine which mediates bone resorption and cartilage destruction by inducing MAPK signal transduction in RA. The present studies investigated the relationship between G protein associated signal transduction pathway and MAPK cascades in AA-derived FLS stimulated by IL-1 and the effects of TGP on Adjuvants arthritis (AA).OBJECTIVE MAPKs cascades in fibroblast-like synoviocytes (FLS) induced bypro-inflammatory cytokines such as IL-1 can be activated by G-proteins -coupled signal ways in RA. This study was to elucidate the relationship between G protein-associated transmembrane cascades and MAPKs signal transduction pathways in recombinant rat IL-1 a (rIL-1 a )-induced FLS from rats with AA. This study was to investigate the relationship between ultrastructure of synoviocytes and its secretory function and the relationship between different types of synoviocytes. The study was also to extend our understanding of the roles played by TGP in the pathogenesis of arthritic diseases and to develop a new therapeutic strategy for the treatment of rheumatoid arthritis (RA) by blockade of cytokine-signaling pathways in synoviocytes.MATHODS (1) The expressions of MAPKs phosphorylation, matrixmetalloproteinases (MMPs), cyclooxygenase (COX) , the stimulatory subunit of G alpha protein (Gs) and the inhibitory subunit of G alpha protein (G;) were detected by Western blot in rIL-1 a -induced FLS that treated with cholera toxin (CT), pertussis toxin (PT), SB 203580(a selective inhibitor of c-Jun N-terminal kinase (JNK)/p38 cascades) and U 0126(a selective inhibitor of extracellular regulating kinase (ERK) cascade), respectively. While cAMP accumulation was measured by enzyme-linked immuno-absorbant assay (ELISA) and prostaglandin E2 (PGE2) was measured by radioimmunoassay. The activities of protein kinase A (PKA) and PKC were detected by ELISA.(2) AA in rats was established and hind paw volumes of rats were measured by
volume meter. Before the onset of arthritis, animals were divided into eight groups randomly. Rats were given intragastrically TGP (25, 50, 100 mg ■ kg'1, once per day) or given an intracutaneous injection of IL-lra (2.5, 10, 40 mg ? kg"1, thrice per day) from days 14 to 21 after immunization. For the normal and AA model, rats were given an equal volume of vehicle. Synoviocytes proliferation and the activity of IL-1 were determined by MTT assay. Tumor necrosis factor alpha (TNF-a) and PGE2 were measured by radioimmunoassay. Ultrastructure of synovioctes was observed under transmission electron microscope. The phosphorylation of JNK, ERK and p38 kinase and the expressions of MMPs, Gs and Gi were detected by Western blot analysis. The activities of PKA and PKC were detected by ELISARESULTS1. Relationship between G- proteins associated transmembrane cascades and MAPK cascades in rat AA-derived FLS stimulated by rIL-la(1) Relationship between a subunits of G- proteins and MAPK cascades induced by rIL-la in rat AA-derived FLSrIL-la induced phosphorylation of ERK, JNK, and p38 at 20 min in rat AA-derived FLS. PT(1 11 g - ml"1) and CT (10 u g . ml"1) inhibited phosphorylation of ERK, JNK, and p38 induced by rIL-la. Further studies found that U 0126 (25 and 50 V M) and SB 203580(2.5 and 25 u M)decreased the expressions of Gu, Gj2, Gj3 and Gs induced by rIL-1 a in rat AA-derived FLS.(2) Effects of MAPKs cascades on G protein-cAMP signal pathway in rat AA-derived FLS activated by rIL-la.rIL-1 a decreased intracellular cAMP levels from Omin to 30 min, and it increased intracellular cAMP levels from 30 min to 150 min. rIL-1 a also induced accumulation of extracellular PGE2 production by FLS. SB 203580(2.5 and 25 u M) and U0126 (25 u M) decreased the cAMP and PGE2 accumulation induced by rIL-la. Exogenously PGE2 (10, 50 and 100 pg ? ml'1) increased the cAMP levels inhibited by U0126 and SB203580 in a concentration-dependent manner. The data ruled out the possibility that the effects of U 0126 and SB 203580 may be due to inhibit the rIL-1 a
-induced production of PGE2(3) Effects of MAPKs cascades on G protein-PKA signal and G protein-PKC signal in rat AA-derived FLS activated by rIL-la.Compared with those in rat AA-derived FLS, the activities of PKA PKC and PKC /PKA increased significantly in AA FLS induced by rIL-1 a (lOng . ml*1) for 150 min. SB 203580 (2.5 and 25 u M) and U0126 (25 u M) not only decreased the activities of PKC and PKA but also decreased the PKC/PKA in rat AA-derived FLS stimulated by rIL-1 a .(4) Effects of G- proteins associated cascades and MAPK cascades induced by rIL-la on function of rat AA-derived FLSThe expression of MMP-K MMP-3 and COX-2 increased significantly in rat AA-derived FLS induced by rIL-1 a and was inhibited by PT, CT, SB203580 or 10126. The inhibitors had no significant effect on expression of COX-1. The results demonstrate that G- proteins associated cascades and MAPK cascades make important roles on function of rat AA-derived FLS.2. Effects of TGP on G- proteins associated cascades and MAPK cascades in synoviocytes from rats with AA(1) Effects of TGP on secondary inflammatory reaction, body weight and histopathology of AA ratsInflammatory polyarthritis was induced in all immunized rats. The paw swelling occurred on d 13 after immunizatioa Treatment with TGP (25, 50, 100 mg ? kg'1, ig, days 14-21) diminished the right hind paw swelling and polyarthritic symptoms on d 17 and d21 after immunization. The administration of TGP (50 and 100 mg ? kg'1, ig, days 14-21) increased significantly the body weight of AA rats on d 17 and the same efficacy of TGP (50 mg ? kg"1) were observed on d 21 after immunization.In AA rats, synoviocytes proliferated three to four layers and became ovalis types, and articular cartilages were destructed and infiltrated with inflammatory cells. The hyperplastic synovium in AA rat formed a large number of fibroblasts and new blood vessels. Proliferation of collagen fribrils was found under synoviums of AA rats. In AA rats given TGP intragastrically, the synovial hyperplasia was inhibited and the
destruction of articular cartilages was alleviated.(2) Effect of TGP on ultrastructure of synoviocytes and cytokines production by Macrophage-like synoviocytes (MLS) from AA ratsThe intracellular changes were observed in AA rats, including that extracellular matrix and collagen increased, Golgi bodies reduced in size and curled, mitochondria swelled with ridges decreasing, rough endoplasmic reticulum (RER) increased and dilated, dense bodies and vacuoles increased. TGP (50 and 100 mg . kg'1, ig, days 14-21) repaired the injury mentioned above to some extent and decreased significantly the production of IL-1, PGE2and TNF-a by MLS from AA. The results suggested that TGP reduced the second inflammatory in AA rats, which was associated with prevention of ultrastructural of synoviocytes and inhibition of secretion of proimfiammatory cytokines.(3) Effects of TGP on phosphorylation of MAPKs, cell proliferation and MMPs production in rat-AA derived synoviocytesTGP (50 and lOOmg . kg"1, ig, days 14-21) inhibited phosphorylation of MAPKs in synovial membrane of AA rats. Furthermore, supernatants of MLS from AA rats induced more phosphorylation of MAPKs including JNK, ERK and p38 in AA FLS than that from normal rats. The surpernatents of MLS from AA rats treated with TGP (50 and 100 mg ? kg"1, ig, days 14-21) induced less phosphorylation of MAPKs in AA FLS than that from AA rats.Compared with supernatants of normal MLS, the supernatants of AA MLS increased cell proliferation and expression of MMP-1 and MMP-3 in AA FLS. The surpernatents of MLS from AA rats treated with TGP (50 or 100 mg . kg"1, ig, days 14-21) induced less production of MMP-1 and MMP-3 and decreased cell proliferation in AA FLS than that from AA rats.(4) Effects of TGP on G protein associated signal pathways in rat-AA derived FLS stimulated by rIL-1 aTGP (2.5 and 12.5 mg ■ L"1) decreased expressions of Gil, Gi2 and Gi3 in AA FLS stimulated by rIL-1 a . Furthermore, TGP (2.5 and 12.5 mg - L'1) not only increased the the activities of PKA but also decreased the activities of PKC and
Rheumatoid arthritis (RA) is one of the most serious medical problems affecting approximately 1 ~ 1.5 % of all people worldwide. A major obstacle to the development of rational treatment strategies is that the disease mechanisms remain largely unknown and clues may come from experimental arthritis. The disease is autoimmune in nature and characterized by chronic inflammation of the synovial tissues in multiple joints that leads to joint destruction. Although palliative treatments are widely prescribed, there are currently only a few treatments that can modify the progression of the disease.Total glucosides of paeony (TGP) is an active compound extracted from roots of paeonia lactiflora Pall which have been recognized as the valuable traditional herbs used in treatment for rheumatoid arthritis (RA) and hepatitis with a long history in traditional Chinese medicine. TGP contains more than 40% percentage of paeoniflorin and other components such as hydroxy-paeoniflorin, paeonin, albiflorin, benzoylpaeoniflorin, et al. It has anti-inflammatory and immune-regulatory effects and has been approved by State Food and Drug Administration (SFDA) for the treatment of RA as a disease-modifying drug.Signaling through stress- and mitogen-activated protein kinases (SAPK/MAPK) pathways in FLS is a typical feature of chronic synovitis in RA. As well known, various MAPK cascades can be activated by guanine nucleotide binding regulatory proteins (G proteins)-coupled receptors (GPCRs)/G-protein components. Thus, the
cytokine-signaling including G protein transmembrane signal and MAPKs pathway became new targets for treatment of RA. Interleukin-1 (IL-1) is an important pro-inflammation cytokine which mediates bone resorption and cartilage destruction by inducing MAPK signal transduction in RA. The present studies investigated the relationship between G protein associated signal transduction pathway and MAPK cascades in AA-derived FLS stimulated by IL-1 and the effects of TGP on Adjuvants arthritis (AA).OBJECTIVE MAPKs cascades in fibroblast-like synoviocytes (FLS) induced bypro-inflammatory cytokines such as IL-1 can be activated by G-proteins -coupled signal ways in RA. This study was to elucidate the relationship between G protein-associated transmembrane cascades and MAPKs signal transduction pathways in recombinant rat IL-1 a (rIL-1 a )-induced FLS from rats with AA. This study was to investigate the relationship between ultrastructure of synoviocytes and its secretory function and the relationship between different types of synoviocytes. The study was also to extend our understanding of the roles played by TGP in the pathogenesis of arthritic diseases and to develop a new therapeutic strategy for the treatment of rheumatoid arthritis (RA) by blockade of cytokine-signaling pathways in synoviocytes.MATHODS (1) The expressions of MAPKs phosphorylation, matrixmetalloproteinases (MMPs), cyclooxygenase (COX) , the stimulatory subunit of G alpha protein (Gs) and the inhibitory subunit of G alpha protein (G;) were detected by Western blot in rIL-1 a -induced FLS that treated with cholera toxin (CT), pertussis toxin (PT), SB 203580(a selective inhibitor of c-Jun N-terminal kinase (JNK)/p38 cascades) and U 0126(a selective inhibitor of extracellular regulating kinase (ERK) cascade), respectively. While cAMP accumulation was measured by enzyme-linked immuno-absorbant assay (ELISA) and prostaglandin E2 (PGE2) was measured by radioimmunoassay. The activities of protein kinase A (PKA) and PKC were detected by ELISA.(2) AA in rats was established and hind paw volumes of rats were measured by
volume meter. Before the onset of arthritis, animals were divided into eight groups randomly. Rats were given intragastrically TGP (25, 50, 100 mg ■ kg'1, once per day) or given an intracutaneous injection of IL-lra (2.5, 10, 40 mg ? kg"1, thrice per day) from days 14 to 21 after immunization. For the normal and AA model, rats were given an equal volume of vehicle. Synoviocytes proliferation and the activity of IL-1 were determined by MTT assay. Tumor necrosis factor alpha (TNF-a) and PGE2 were measured by radioimmunoassay. Ultrastructure of synovioctes was observed under transmission electron microscope. The phosphorylation of JNK, ERK and p38 kinase and the expressions of MMPs, Gs and Gi were detected by Western blot analysis. The activities of PKA and PKC were detected by ELISARESULTS1. Relationship between G- proteins associated transmembrane cascades and MAPK cascades in rat AA-derived FLS stimulated by rIL-la(1) Relationship between a subunits of G- proteins and MAPK cascades induced by rIL-la in rat AA-derived FLSrIL-la induced phosphorylation of ERK, JNK, and p38 at 20 min in rat AA-derived FLS. PT(1 11 g - ml"1) and CT (10 u g . ml"1) inhibited phosphorylation of ERK, JNK, and p38 induced by rIL-la. Further studies found that U 0126 (25 and 50 V M) and SB 203580(2.5 and 25 u M)decreased the expressions of Gu, Gj2, Gj3 and Gs induced by rIL-1 a in rat AA-derived FLS.(2) Effects of MAPKs cascades on G protein-cAMP signal pathway in rat AA-derived FLS activated by rIL-la.rIL-1 a decreased intracellular cAMP levels from Omin to 30 min, and it increased intracellular cAMP levels from 30 min to 150 min. rIL-1 a also induced accumulation of extracellular PGE2 production by FLS. SB 203580(2.5 and 25 u M) and U0126 (25 u M) decreased the cAMP and PGE2 accumulation induced by rIL-la. Exogenously PGE2 (10, 50 and 100 pg ? ml'1) increased the cAMP levels inhibited by U0126 and SB203580 in a concentration-dependent manner. The data ruled out the possibility that the effects of U 0126 and SB 203580 may be due to inhibit the rIL-1 a
-induced production of PGE2(3) Effects of MAPKs cascades on G protein-PKA signal and G protein-PKC signal in rat AA-derived FLS activated by rIL-la.Compared with those in rat AA-derived FLS, the activities of PKA PKC and PKC /PKA increased significantly in AA FLS induced by rIL-1 a (lOng . ml*1) for 150 min. SB 203580 (2.5 and 25 u M) and U0126 (25 u M) not only decreased the activities of PKC and PKA but also decreased the PKC/PKA in rat AA-derived FLS stimulated by rIL-1 a .(4) Effects of G- proteins associated cascades and MAPK cascades induced by rIL-la on function of rat AA-derived FLSThe expression of MMP-K MMP-3 and COX-2 increased significantly in rat AA-derived FLS induced by rIL-1 a and was inhibited by PT, CT, SB203580 or 10126. The inhibitors had no significant effect on expression of COX-1. The results demonstrate that G- proteins associated cascades and MAPK cascades make important roles on function of rat AA-derived FLS.2. Effects of TGP on G- proteins associated cascades and MAPK cascades in synoviocytes from rats with AA(1) Effects of TGP on secondary inflammatory reaction, body weight and histopathology of AA ratsInflammatory polyarthritis was induced in all immunized rats. The paw swelling occurred on d 13 after immunizatioa Treatment with TGP (25, 50, 100 mg ? kg'1, ig, days 14-21) diminished the right hind paw swelling and polyarthritic symptoms on d 17 and d21 after immunization. The administration of TGP (50 and 100 mg ? kg'1, ig, days 14-21) increased significantly the body weight of AA rats on d 17 and the same efficacy of TGP (50 mg ? kg"1) were observed on d 21 after immunization.In AA rats, synoviocytes proliferated three to four layers and became ovalis types, and articular cartilages were destructed and infiltrated with inflammatory cells. The hyperplastic synovium in AA rat formed a large number of fibroblasts and new blood vessels. Proliferation of collagen fribrils was found under synoviums of AA rats. In AA rats given TGP intragastrically, the synovial hyperplasia was inhibited and the
destruction of articular cartilages was alleviated.(2) Effect of TGP on ultrastructure of synoviocytes and cytokines production by Macrophage-like synoviocytes (MLS) from AA ratsThe intracellular changes were observed in AA rats, including that extracellular matrix and collagen increased, Golgi bodies reduced in size and curled, mitochondria swelled with ridges decreasing, rough endoplasmic reticulum (RER) increased and dilated, dense bodies and vacuoles increased. TGP (50 and 100 mg . kg'1, ig, days 14-21) repaired the injury mentioned above to some extent and decreased significantly the production of IL-1, PGE2and TNF-a by MLS from AA. The results suggested that TGP reduced the second inflammatory in AA rats, which was associated with prevention of ultrastructural of synoviocytes and inhibition of secretion of proimfiammatory cytokines.(3) Effects of TGP on phosphorylation of MAPKs, cell proliferation and MMPs production in rat-AA derived synoviocytesTGP (50 and lOOmg . kg"1, ig, days 14-21) inhibited phosphorylation of MAPKs in synovial membrane of AA rats. Furthermore, supernatants of MLS from AA rats induced more phosphorylation of MAPKs including JNK, ERK and p38 in AA FLS than that from normal rats. The surpernatents of MLS from AA rats treated with TGP (50 and 100 mg ? kg"1, ig, days 14-21) induced less phosphorylation of MAPKs in AA FLS than that from AA rats.Compared with supernatants of normal MLS, the supernatants of AA MLS increased cell proliferation and expression of MMP-1 and MMP-3 in AA FLS. The surpernatents of MLS from AA rats treated with TGP (50 or 100 mg . kg"1, ig, days 14-21) induced less production of MMP-1 and MMP-3 and decreased cell proliferation in AA FLS than that from AA rats.(4) Effects of TGP on G protein associated signal pathways in rat-AA derived FLS stimulated by rIL-1 aTGP (2.5 and 12.5 mg ■ L"1) decreased expressions of Gil, Gi2 and Gi3 in AA FLS stimulated by rIL-1 a . Furthermore, TGP (2.5 and 12.5 mg - L'1) not only increased the the activities of PKA but also decreased the activities of PKC and
引文
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33. Zhu F, Zhang Y, Bode AM, Dong Z. Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Carcinogenesis, 2004; 25(10): 1847-1852.
34. Harigai M, Hara M, Kawamoto M, Kawaguchi Y, Sugiura T, Tanaka M, Nakagawa M, Ichida H, Takagi K, Higami-Ohsako S, Shimada K, Kamatani N.Amplification of the synovial inflammatory response through activation of mitogen-activated protein kinases and nuclear factor kappaB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis. Arthritis Rheum, 2004; 50(7): 2167-2177.
35. Rosengren S, Hoffman H, Bugbee W, Boyle DL. Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Ann Rheum Dis, 2004; 21(1): 547-552
36. Frost JA, Alberts AS, Sontag E, Guan K, Mumby MC, Feramisco JR. Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. Mol Cell Biol, 1994; 14 (9) : 6244-6252
37. Keyse, S. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol, 2000; 12 (2) : 186-192.
38. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci, 1999; 24(5): 186-191.
39. Virshup DM. Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol, 2000;12 (2) : 180-185.
40. Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, Zenz P, Redlich K, Xu Q, Steiner G Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum, 2000; 43(11): 2501-2512
41. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest, 2001; 108(l):73-81.
42. Min SY, Hwang SY, Jung YO, Jeong J, Park SH, Cho CS, Kim HY, Kim WU. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Rheumatol. 2004; 31(5): 875-883.
43. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS. Jun N-Terminal Kinase in Rheumatoid Arthritis. 1999; 291(1): 124-130.
44. Foster ML, Halley F, Souness JE. Potential of p38 inhibitors in the treatment of rheumatoid arthritis. Drug News Perspect, 2000; 13(8): 488-497.
45. Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum, 2003; 48(9): 2670-2681.
46. Stork PJS and Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. TRENDS, 2002; 12(6): 258-266.
47. Mochan E, Ross B, Sporer R, Uhl J. Interleukin-1 mediated signal transduction associated with synovial cell activation. Agents Actions, 1989; 27(3): 282-284
48. Kim G, Jun JB, Elkon KB. Necessary role of phosphatidylinositol 3-kinase in transforming growth factor beta-mediated activation of Akt in normal and rheumatoid arthritis synovial fibroblasts. Arthritis Rheum, 2002; 46(6): 1504-1511
49. Vogler O, Casas J, Capo D, Nagy T, Borchert G, Martorell G, Escriba PV. The Gbetagamma dimer drives the interaction of heterotrimeric Gi proteins with nonlamellar membrane structures. J Biol Chem, 2004; 279(35): 36540-36545.
50. Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol, 2001; 167(9): 5381-5385.
51. Case JP, Lafyatis R, Kumkumian GK, Remmers EF, Wilder RL. IL-1 regulation of
??transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. J Immunol, 1990; 145(11): 3755-3761.
52. DiBattista JA, Martel-Pelletier J, Fujimoto N, Obata K, Zafarullah M, Pelletier JP. Prostaglandins E2 and El inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway. Lab Invest, 1994; 71(2): 270-278.
53. Inoue H, Takamori M, Shimoyama Y, Ishibashi H, Yamamoto S, Koshihara Y. Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts. Br J Pharmacol, 2002; 136(2): 287-295.
54. Ruddy S, Harris ED, Sledge CB, Kelley WN. Kelley's textbook of rheumatology. W.B. Saunders(Ed). Newyork: Co. Philadelphia Pennsylvania, 2001; pp1904.
55. Muro H, Waguri-Nagaya Y, Mukofujiwara Y, Iwahashi T, Otsuka T, Matsui N, Moriyama A, Asai K, Kato T. Autocrine induction of gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) and GLS-induced expression of matrix metalloproteinases in rheumatoid arthritis synoviocytes Rheumatology 1999; 38(12): 1195-1202
56. Inoue K, Masuko-Hongo K, Okamoto M, Nishioka K. Induction of vascular endothelial growth factor and matrix metalloproteinase-3 (stromelysin) by interleukin-1 in human articular chondrocytes and synoviocytes. Rheumatol Int, 2004; 29(9): [Epub ahead of print]
57. Suzuki K, Rapuano BE, Bockman RS. Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82. J Bone Miner Res, 1997; 12(4): 561-567.
58. Pillinger MH, Rosenthal PB, Tolani SN, Apsel B, Dinsell V, Greenberg J, Chan ES, Gomez PF, Abramson SB. Cyclooxygenase-2-derived E prostaglandins down-regulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via inhibition of extracellular signal-regulated kinase activation. J
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7. Faour WH, He Y, He QW, de Ladurantaye M, Quintero M. Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2 mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1 beta-treated human synovial fibroblasts. J Biol Chem, 2001; 276(34): 31720-31731
8. Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum, 2000; 43(11): 2501-2512
9. Naor Z, Benard O, Seger R. Activation of MAPK Cascades by G-protein-coupled Receptors: The Case of Gonadotropin-releasing Hormone Receptor. TEM, 2000; 11(1): 91-99
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12. Nakamura H, Shibakawa A, Tanaka M, Kato T, Nishioka K. Effects of glucosamine hydrochloride on the production of prostaglandin E2, nitric oxide and metalloproteases by chondrocytes and synoviocytes in osteoarthritis. Clin Exp Rheumatol, 2004; 22(3): 293-299
13. Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S. Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum, 2003; 48 (9): 2682-2692.
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16. Dai M, Wei W, Shen YX, Zheng YQ. Glucosides of Chaenomeles speciosa remit rat adjuvant arthritis by inhibiting synoviocyte activities. Acta Pharmacol Sin, 2003; 24(11): 1161-1166.
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26. Demasi M, Cleland LG, Cook-Johnson RJ, James MJ. Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast-like synoviocytes: interactions with monocyte-derived soluble mediators. Arthritis Rheum, 2004; 50(8): 2441-2449
27. Rinaldi N, Willhauck M, Weis D, Brado B, Kern P, Lukoschek M, Schwarz-Eywill M, Barth TF. Loss of collagen type IV in rheumatoid synovia and cytokine effect on the collagen type-Ⅳ gene expression in fibroblast-like synoviocytes from rheumatoid arthritis. Virchows Arch, 2001; 439(5): 675-682
28. Georganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B, Pope RM. Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol, 2000; 165(12): 7199-7206
29. Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S. Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum, 2003; 48(9): 2682-2692
30. Lu H, Sun T, Yao L, Zhang Y. Role of protein tyrosine kinase in IL-1 beta induced activation of mitogen-activated protein kinase in fibroblast-like synoviocytes of rheumatoid arthritis. Chin Med J, 2000; 113(10): 872-876
31. Niki Y, Yamada H, Kikuchi T, Toyama Y, Matsumoto H, Fujikawa K, Tada N. Membrane-associated IL-1 contributes to chronic synovitis and cartilage destruction in human IL-1 alpha transgenic mice. J Immunol, 2004; 172(1): 577-584.
32. Firestein GS, Boyle DL, Yu C, Paine MM, Whisenand TD, Zvaifler NJ, Arend WP Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum, 1994; 37(5): 644-652
33. Zhu F, Zhang Y, Bode AM, Dong Z. Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Carcinogenesis, 2004; 25(10): 1847-1852.
34. Harigai M, Hara M, Kawamoto M, Kawaguchi Y, Sugiura T, Tanaka M, Nakagawa M, Ichida H, Takagi K, Higami-Ohsako S, Shimada K, Kamatani N.Amplification of the synovial inflammatory response through activation of mitogen-activated protein kinases and nuclear factor kappaB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis. Arthritis Rheum, 2004; 50(7): 2167-2177.
35. Rosengren S, Hoffman H, Bugbee W, Boyle DL. Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Ann Rheum Dis, 2004; 21(1): 547-552
36. Frost JA, Alberts AS, Sontag E, Guan K, Mumby MC, Feramisco JR. Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. Mol Cell Biol, 1994; 14 (9) : 6244-6252
37. Keyse, S. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol, 2000; 12 (2) : 186-192.
38. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci, 1999; 24(5): 186-191.
39. Virshup DM. Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol, 2000;12 (2) : 180-185.
40. Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, Zenz P, Redlich K, Xu Q, Steiner G Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum, 2000; 43(11): 2501-2512
41. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest, 2001; 108(l):73-81.
42. Min SY, Hwang SY, Jung YO, Jeong J, Park SH, Cho CS, Kim HY, Kim WU. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Rheumatol. 2004; 31(5): 875-883.
43. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS. Jun N-Terminal Kinase in Rheumatoid Arthritis. 1999; 291(1): 124-130.
44. Foster ML, Halley F, Souness JE. Potential of p38 inhibitors in the treatment of rheumatoid arthritis. Drug News Perspect, 2000; 13(8): 488-497.
45. Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum, 2003; 48(9): 2670-2681.
46. Stork PJS and Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. TRENDS, 2002; 12(6): 258-266.
47. Mochan E, Ross B, Sporer R, Uhl J. Interleukin-1 mediated signal transduction associated with synovial cell activation. Agents Actions, 1989; 27(3): 282-284
48. Kim G, Jun JB, Elkon KB. Necessary role of phosphatidylinositol 3-kinase in transforming growth factor beta-mediated activation of Akt in normal and rheumatoid arthritis synovial fibroblasts. Arthritis Rheum, 2002; 46(6): 1504-1511
49. Vogler O, Casas J, Capo D, Nagy T, Borchert G, Martorell G, Escriba PV. The Gbetagamma dimer drives the interaction of heterotrimeric Gi proteins with nonlamellar membrane structures. J Biol Chem, 2004; 279(35): 36540-36545.
50. Nanki T, Nagasaka K, Hayashida K, Saita Y, Miyasaka N. Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Immunol, 2001; 167(9): 5381-5385.
51. Case JP, Lafyatis R, Kumkumian GK, Remmers EF, Wilder RL. IL-1 regulation of
??transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. J Immunol, 1990; 145(11): 3755-3761.
52. DiBattista JA, Martel-Pelletier J, Fujimoto N, Obata K, Zafarullah M, Pelletier JP. Prostaglandins E2 and El inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway. Lab Invest, 1994; 71(2): 270-278.
53. Inoue H, Takamori M, Shimoyama Y, Ishibashi H, Yamamoto S, Koshihara Y. Regulation by PGE2 of the production of interleukin-6, macrophage colony stimulating factor, and vascular endothelial growth factor in human synovial fibroblasts. Br J Pharmacol, 2002; 136(2): 287-295.
54. Ruddy S, Harris ED, Sledge CB, Kelley WN. Kelley's textbook of rheumatology. W.B. Saunders(Ed). Newyork: Co. Philadelphia Pennsylvania, 2001; pp1904.
55. Muro H, Waguri-Nagaya Y, Mukofujiwara Y, Iwahashi T, Otsuka T, Matsui N, Moriyama A, Asai K, Kato T. Autocrine induction of gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) and GLS-induced expression of matrix metalloproteinases in rheumatoid arthritis synoviocytes Rheumatology 1999; 38(12): 1195-1202
56. Inoue K, Masuko-Hongo K, Okamoto M, Nishioka K. Induction of vascular endothelial growth factor and matrix metalloproteinase-3 (stromelysin) by interleukin-1 in human articular chondrocytes and synoviocytes. Rheumatol Int, 2004; 29(9): [Epub ahead of print]
57. Suzuki K, Rapuano BE, Bockman RS. Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82. J Bone Miner Res, 1997; 12(4): 561-567.
58. Pillinger MH, Rosenthal PB, Tolani SN, Apsel B, Dinsell V, Greenberg J, Chan ES, Gomez PF, Abramson SB. Cyclooxygenase-2-derived E prostaglandins down-regulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via inhibition of extracellular signal-regulated kinase activation. J