Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP.
Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP.
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DOI：
10.4049/jimmunol.0900801
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Kinne RW
中科院分区：
文献类型：
--
作者：
Kunisch E;Jansen A;Kojima F;Löffler I;Kapoor M;Kawai S;Rubio I;Crofford LJ;Kinne RW
本研究探讨PGE2、E prostanoid （EP）受体及其信号通路对类风湿关节炎（RA）滑膜成纤维细胞（SFs）基质金属蛋白酶(MMP)-1和IL-6表达的影响。rasf表达所有四种EP受体，TNF-α选择性诱导EP2。TNF-α时间依赖性地增加细胞内cAMP/蛋白激酶A信号传导（最大，6-12小时）和PGE2分泌（最大，24小时）。PGE2和EP2激动剂butaprost或ONO-AE1-259（(16)-9-脱氧-9β-氯-15-脱氧-16-羟基-17,17-三亚甲基-19,20-二脱氢PGE1）依次诱导cAMP快速，时间依赖性（最大15-30分钟）增加。此外，NS-398 （N-（2-环己基氧基-4-硝基苯基）-甲磺酰胺）抑制环氧化酶-2可降低TNF-α-诱导的IL-6 mRNA/蛋白的升高，而PGE2或EP2、EP3和EP4激动剂刺激可恢复IL-6 mRNA/蛋白的升高。相比之下，TNF-α-诱导的MMP-1分泌不受NS-398的影响，并通过EP2被PGE2减少。最后，3-异丁基-1-甲基黄嘌呤增强了PGE2对MMP-1的影响，但对IL-6 mRNA没有影响。综上所述，PGE2对TNF-α-诱导的促炎IL-6和促破坏MMP-1 mRNA表达的影响与EP受体的使用和对cAMP的依赖有关。虽然特异性阻断EP2受体被认为是一种很有前景的RA治疗策略，但PGE2通过EP2对促炎IL-6和促破坏性MMP-1的相反调节可能需要更复杂的方法来成功抑制环氧化酶-1/2 cAMP轴。
The present study investigated the influence of PGE2, E prostanoid (EP) receptors, and their signaling pathways on matrix metalloproteinase (MMP)-1 and IL-6 expression in synovial fibroblasts (SFs) from rheumatoid arthritis (RA) patients. RASFs expressed all four EP receptors, with selective induction of EP2 by TNF-α. TNF-α time-dependently increased intracellular cAMP/protein kinase A signaling (maximum, 6–12 h) and PGE2 secretion (maximum, 24 h). PGE2 and the EP2 agonists butaprost or ONO-AE1-259 ((16)-9-deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro PGE1), in turn, induced a rapid, time-dependent (maximum, 15–30 min) increase of cAMP. Additionally, cyclooxygenase-2 inhibition by NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide) reduced the TNF-α-induced increase in IL-6 mRNA/protein, which was restored by stimulation with PGE2 or EP2, EP3, and EP4 agonists. In contrast, TNF-α-induced MMP-1 secretion was not influenced by NS-398 and diminished by PGE2 via EP2. Finally, 3-isobutyl-1-methylxanthine enhanced the effects of PGE2 on MMP-1, but not on IL-6 mRNA. In conclusion, PGE2 differentially affects TNF-α-induced mRNA expression of proinflammatory IL-6 and prodestructive MMP-1 regarding the usage of EP receptors and the dependency on cAMP. Although specific blockade of EP2 receptors is considered a promising therapeutic strategy in RA, opposite regulation of proinflammatory IL-6 and prodestructive MMP-1 by PGE2 via EP2 may require more complex approaches to successfully inhibit the cyclooxygenase-1/2 cAMP axis.
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DOI：
10.1186/ar391
发表时间：
2002
期刊：
Arthritis research
影响因子：
--
作者：
Hirth A;Skapenko A;Kinne RW;Emmrich F;Schulze-Koops H;Sack U
通讯作者：
Sack U
影响因子：
4.8
作者：
Fujino, H;Xu, W;Regan, JW
通讯作者：
Regan, JW
影响因子：
4
作者：
Fushimi, Kazunari;Nakashima, Shigeru;Shimizu, Katsuji
通讯作者：
Shimizu, Katsuji
影响因子：
4.8
作者：
Fujino, H;West, KA;Regan, JW
通讯作者：
Regan, JW
影响因子：
7.3
作者：
Inoue, H;Takamori, M;Koshihara, Y
通讯作者：
Koshihara, Y