G蛋白偶联受体激酶在胶原性关节炎大鼠滑膜细胞信号转导中的作用及白芍总苷和芍药苷对其的影响
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摘要
目的:观察胶原性关节炎(collagen-induced arthritis, CIA)大鼠炎症过程中滑膜组织G蛋白偶联受体激酶(G-protein-coupled receptor kinases,GRKs)的表达情况及白芍总苷(total glucosides of paeony, TGP)对其的影响;明确GRKs在CIA大鼠成纤维样滑膜细胞(fibroblast-like synoviocytes, FLS)中的表达情况及TGP中有效单体成分芍药苷(paeoniflorin,Pae)对其的影响。从滑膜细胞G蛋白偶联信号途径,研究GRK2在FLS的信号调节中作用及Pae治疗大鼠CIA的可能的分子机制。
方法:大鼠足趾、尾根部、背部皮内多点注射鸡Ⅱ型胶原(chicken typeⅡcollagen, CCⅡ)乳剂制备CIA模型,TGP(25、50、100 mg·kg-1·d-1)灌胃给药(intragastric administration, ig)(d14～d28),观察大鼠全身状况及足爪肿胀度,光学显微镜观察关节病理变化;Western blot检测GRKs水平。组织块法培养大鼠关节滑膜细胞,微孔生物发光法检测FLS PKA活性,放免法检测FLS cAMP水平。
结果:
1. CIA大鼠关节滑膜组织GRKs的表达及TGP对其的影响
CIA大鼠加强免疫注射后28天左右炎症反应达到高峰,光镜下可见滑膜组织中滑膜细胞增生明显,层次增多,排列紊乱,滑膜下层纤维组织增生,血管扩张、充血,炎性细胞浸润及血管翳形成,软骨中炎性细胞浸润,破坏软骨组织。Westernblot发现CIA大鼠滑膜组织中GRK2、GRK5、GRK6的表达较正常组明显升高,致炎后28天GRK2、GRK5、GRK6的表达达到高峰;46天后关节肿胀、炎症逐渐减退,GRK2、GRK5、GRK6的高表达也开始下降。TGP (25、50、100 mg﹒kg~(-1))可明显减轻CIA大鼠的足爪肿胀度,改善其多发性关节炎症状,可不同程度改善以上病理变化。TGP (25、50、100 mg·kg~(-1))可以降低CIA大鼠滑膜组织GRK5、GRK6的高表达水平;TGP(100 mg·kg-1)给药后CIA大鼠滑膜组织GRK2的表达水平明显降低。
2. GRKs在CIA大鼠滑膜细胞中的表达及Pae对其的影响
CIA大鼠滑膜细胞GRK2、GRK5、GRK6表达水平升高,Pae(10-5、10-6、10-7、10-8mol·L~(-1))可以不同程度的降低CIA大鼠滑膜细胞GRK2、GRK5、GRK6的表达。3.GRK2与G蛋白-AC-cAMP信号通路的关系及Pae对其的影响
加入GRK2抑制剂(5-甲基[2-(5-硝基-2-呋喃基)乙烯基]-2-糠酸酯,C12H9NO6)后,滑膜细胞cAMP的水平和PKA的活性升高;Pae(10-5、10-6、10-7、10-8mol·L~(-1))可以降低GRK2抑制剂引起的滑膜细胞cAMP水平的升高,Pae(10-5、10-6mol·L~(-1))可以降低GRK2抑制剂引起的滑膜细胞PKA活性的升高。
结论:
1. CIA炎症导致关节滑膜组织和滑膜细胞GRK2、GRK5、GRK6表达水平的上调; GRKs是CIA滑膜炎症、滑膜细胞异常增殖的重要分子。
2. TGP对大鼠CIA多发性关节炎、关节局部肿胀及病理形态等具有明显的改善作用;TGP、Pae可以下调CIA大鼠关节滑膜组织和滑膜细胞GRKs的高表达;而且Pae可以纠正GRK2抑制剂引起的CIA大鼠滑膜细胞脱敏障碍,恢复G蛋白-AC-cAMP信号通路的正常转导。提示TGP、Pae下调GRKs的表达,抑制GPCRs的过度脱敏,调节G蛋白-AC-cAMP信号通路的正常转导,可能是其抑制滑膜细胞增殖、维持滑膜正常功能的重要机制之一。
OBJECTIVE To investigate the expression changes of GRKs in synovium from CIA rats during the inflamation and the effects of TGP. Then we clarified the expression of GRKs in synoviocytes from CIA rats and the effects of Pae, and we attempted to investigate the role of GRK2 playing in G-Protein signal transduction pathways of synoviocyte and the effects of Pae. And further to analyze the relationship between the effects of Pae on CIA rats and its relative mechanisms by which Pae affected the process of synoviocytes through these signal transduction pathways.
METHODS The model of rat CIA was induced by injection of chicken typeⅡcollagen(CCⅡ) emulsion. TGP(25、50、100 mg·kg~(-1), ig, d14-d28) was administrated intragastric to CIA rats . Hind paw volumes of rats were measured by volume meter. Pathological changes in synovium of joint were observed by light microscope. The expression of GRKs in synoviocytes from CIA rats was measured by western blot. The expression change of cAMP was investigated by radioimmunoassay, and the activities of PKA was measured by luminescent kinase assay.
RESULTS
(1)Expression changes of GRKs in synovium from CIA rats during the inflamation and the effecrs of TGP
Inflammatory reaction occurred on d14 after immunization. There was a marked secondary inflammatory response in the models, which accompanied with paw swelling, pain, polyarthritis, decrease of body weight, and the development of inflammatory lesions. Compared with the normal rats, in CIA rats, the histological morphological examination of rats knee joints showed hyperplastic synovium, synovial lining hyperplasia, inflammatory cells infiltration, pannus formation and destruction of the cartilage, and fatty changes in the synoviocytes. At the inflammatory process (d14～d28 after immunization), we observed a profound up-regulation of GRKs’in synovium from CIA rats and during the remission phase (d46 after immunization), GRKs’expression is returning to baseline levels. TGP (25、50、100 mg·kg-1, ig, d14-28) diminished the right hind paw swelling and polyarthritic symptoms. TGP (25、50、100 mg·kg-1) the expression of GRK5、GRK6 in synovium from CIA rats. TGP(100 mg·kg-1)could decrease the expression of GRK2.
(2)Expression of GRKs in synoviocytes from CIA rats and the effecrs of Pae
Expression of GRK2、GRK5、GRK6 in synoviocytes from CIA rats was increased, Pae(10-5、10-6、10-7、10-8 mol·L~(-1))in vitro could suppress the expression of GRK2、GRK5、GRK6 in synoviocytes from CIA rats.
(3)Role of GRK2 in GPCR-AC-cAMP signaling transduction and the effects of Pae
Level of cAMP and activity of PKA increased in synoviocytes from CIA rats after GRK2 inhibito(rMethyl 5-[2-(5-nitro-2-furyl)vinyl]-2-furoate,C12H9NO6)were given. Pae(10-5、10-6、10-7、10-8 mol·L~(-1)) may decrease the level of cAMP and Pae(10-5、10-6mol·L~(-1))might suppress the activity of PKA.
CONCLUSIONS
(1)An inflammatory process in vivo induces an up-regulation of GRKs in synovium and synoviocytes from CIA rats. The up-regulation of GRKs may play an important role in proliferation of synoviocytes from CIA rats.
(2)TGP can diminish the paw swelling and polyarthritic symptoms, and decrease the expression of GRKs in synovium from CIA rats.In Synoviocytes of CIA rats,Pae may suppress the up-regulation of GRK2、GRK5 and GRK6,and at the same time recover the disorder of desensitization induced by GRK2 inhibitor. Which indicates that TGP、Pae can suppress over-desensitization of synoviocytes from CIA rats, and regulate desensitization of synoviocytes, which may be one of the important mechanisms for the effects of Pae on synoviocytes.
方法:大鼠足趾、尾根部、背部皮内多点注射鸡Ⅱ型胶原(chicken typeⅡcollagen, CCⅡ)乳剂制备CIA模型,TGP(25、50、100 mg·kg-1·d-1)灌胃给药(intragastric administration, ig)(d14～d28),观察大鼠全身状况及足爪肿胀度,光学显微镜观察关节病理变化;Western blot检测GRKs水平。组织块法培养大鼠关节滑膜细胞,微孔生物发光法检测FLS PKA活性,放免法检测FLS cAMP水平。
结果:
1. CIA大鼠关节滑膜组织GRKs的表达及TGP对其的影响
CIA大鼠加强免疫注射后28天左右炎症反应达到高峰,光镜下可见滑膜组织中滑膜细胞增生明显,层次增多,排列紊乱,滑膜下层纤维组织增生,血管扩张、充血,炎性细胞浸润及血管翳形成,软骨中炎性细胞浸润,破坏软骨组织。Westernblot发现CIA大鼠滑膜组织中GRK2、GRK5、GRK6的表达较正常组明显升高,致炎后28天GRK2、GRK5、GRK6的表达达到高峰;46天后关节肿胀、炎症逐渐减退,GRK2、GRK5、GRK6的高表达也开始下降。TGP (25、50、100 mg﹒kg~(-1))可明显减轻CIA大鼠的足爪肿胀度,改善其多发性关节炎症状,可不同程度改善以上病理变化。TGP (25、50、100 mg·kg~(-1))可以降低CIA大鼠滑膜组织GRK5、GRK6的高表达水平;TGP(100 mg·kg-1)给药后CIA大鼠滑膜组织GRK2的表达水平明显降低。
2. GRKs在CIA大鼠滑膜细胞中的表达及Pae对其的影响
CIA大鼠滑膜细胞GRK2、GRK5、GRK6表达水平升高,Pae(10-5、10-6、10-7、10-8mol·L~(-1))可以不同程度的降低CIA大鼠滑膜细胞GRK2、GRK5、GRK6的表达。3.GRK2与G蛋白-AC-cAMP信号通路的关系及Pae对其的影响
加入GRK2抑制剂(5-甲基[2-(5-硝基-2-呋喃基)乙烯基]-2-糠酸酯,C12H9NO6)后,滑膜细胞cAMP的水平和PKA的活性升高;Pae(10-5、10-6、10-7、10-8mol·L~(-1))可以降低GRK2抑制剂引起的滑膜细胞cAMP水平的升高,Pae(10-5、10-6mol·L~(-1))可以降低GRK2抑制剂引起的滑膜细胞PKA活性的升高。
结论:
1. CIA炎症导致关节滑膜组织和滑膜细胞GRK2、GRK5、GRK6表达水平的上调; GRKs是CIA滑膜炎症、滑膜细胞异常增殖的重要分子。
2. TGP对大鼠CIA多发性关节炎、关节局部肿胀及病理形态等具有明显的改善作用;TGP、Pae可以下调CIA大鼠关节滑膜组织和滑膜细胞GRKs的高表达;而且Pae可以纠正GRK2抑制剂引起的CIA大鼠滑膜细胞脱敏障碍,恢复G蛋白-AC-cAMP信号通路的正常转导。提示TGP、Pae下调GRKs的表达,抑制GPCRs的过度脱敏,调节G蛋白-AC-cAMP信号通路的正常转导,可能是其抑制滑膜细胞增殖、维持滑膜正常功能的重要机制之一。
OBJECTIVE To investigate the expression changes of GRKs in synovium from CIA rats during the inflamation and the effects of TGP. Then we clarified the expression of GRKs in synoviocytes from CIA rats and the effects of Pae, and we attempted to investigate the role of GRK2 playing in G-Protein signal transduction pathways of synoviocyte and the effects of Pae. And further to analyze the relationship between the effects of Pae on CIA rats and its relative mechanisms by which Pae affected the process of synoviocytes through these signal transduction pathways.
METHODS The model of rat CIA was induced by injection of chicken typeⅡcollagen(CCⅡ) emulsion. TGP(25、50、100 mg·kg~(-1), ig, d14-d28) was administrated intragastric to CIA rats . Hind paw volumes of rats were measured by volume meter. Pathological changes in synovium of joint were observed by light microscope. The expression of GRKs in synoviocytes from CIA rats was measured by western blot. The expression change of cAMP was investigated by radioimmunoassay, and the activities of PKA was measured by luminescent kinase assay.
RESULTS
(1)Expression changes of GRKs in synovium from CIA rats during the inflamation and the effecrs of TGP
Inflammatory reaction occurred on d14 after immunization. There was a marked secondary inflammatory response in the models, which accompanied with paw swelling, pain, polyarthritis, decrease of body weight, and the development of inflammatory lesions. Compared with the normal rats, in CIA rats, the histological morphological examination of rats knee joints showed hyperplastic synovium, synovial lining hyperplasia, inflammatory cells infiltration, pannus formation and destruction of the cartilage, and fatty changes in the synoviocytes. At the inflammatory process (d14～d28 after immunization), we observed a profound up-regulation of GRKs’in synovium from CIA rats and during the remission phase (d46 after immunization), GRKs’expression is returning to baseline levels. TGP (25、50、100 mg·kg-1, ig, d14-28) diminished the right hind paw swelling and polyarthritic symptoms. TGP (25、50、100 mg·kg-1) the expression of GRK5、GRK6 in synovium from CIA rats. TGP(100 mg·kg-1)could decrease the expression of GRK2.
(2)Expression of GRKs in synoviocytes from CIA rats and the effecrs of Pae
Expression of GRK2、GRK5、GRK6 in synoviocytes from CIA rats was increased, Pae(10-5、10-6、10-7、10-8 mol·L~(-1))in vitro could suppress the expression of GRK2、GRK5、GRK6 in synoviocytes from CIA rats.
(3)Role of GRK2 in GPCR-AC-cAMP signaling transduction and the effects of Pae
Level of cAMP and activity of PKA increased in synoviocytes from CIA rats after GRK2 inhibito(rMethyl 5-[2-(5-nitro-2-furyl)vinyl]-2-furoate,C12H9NO6)were given. Pae(10-5、10-6、10-7、10-8 mol·L~(-1)) may decrease the level of cAMP and Pae(10-5、10-6mol·L~(-1))might suppress the activity of PKA.
CONCLUSIONS
(1)An inflammatory process in vivo induces an up-regulation of GRKs in synovium and synoviocytes from CIA rats. The up-regulation of GRKs may play an important role in proliferation of synoviocytes from CIA rats.
(2)TGP can diminish the paw swelling and polyarthritic symptoms, and decrease the expression of GRKs in synovium from CIA rats.In Synoviocytes of CIA rats,Pae may suppress the up-regulation of GRK2、GRK5 and GRK6,and at the same time recover the disorder of desensitization induced by GRK2 inhibitor. Which indicates that TGP、Pae can suppress over-desensitization of synoviocytes from CIA rats, and regulate desensitization of synoviocytes, which may be one of the important mechanisms for the effects of Pae on synoviocytes.
引文
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