Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis
Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis
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DOI：
10.1002/art.23453
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发表时间：
2008-05-01
影响因子：
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通讯作者：
Lee, David M.
中科院分区：
文献类型：
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作者：
Chen, Mei;Boilard, Eric;Lee, David M.
目标。类风湿关节炎患者关节液中前列腺素(PGs)水平较高，对这些生物活性脂类的非类固醇阻断在治疗中起着重要作用。本研究的目的是探讨环氧合酶(COX)亚型和PG物种在自身抗体驱动的K/BxN血清转移性关节炎中的相对作用。在踝关节匀浆中评估了关节炎踝关节的前列腺素含量，并通过药物阻断证实了这一途径的重要性。用Western blotting检测COX亚型的存在，并用COX-1(-/-)和COX-2(-/-)小鼠以及同型异构体特异性抑制物比较它们的功能贡献。在微粒体前列腺素E合成酶1(mPGES-1)缺陷小鼠和前列腺素I(2)受体中，测定了PGE(2)和前列环素(PGI(2))的相对重要性。在关节炎关节组织中检测到高水平的PGE(2)和6-keto-PGF(1α)(PGI(2)的稳定代谢产物)，并与滑膜炎症的程度密切相关。药物抑制PG合成可预防关节炎，改善活动期疾病。虽然在发炎的关节组织中发现了这两种COX亚型，但只有COX-1对临床疾病有很大贡献；COX-1(-/-)小鼠对疾病完全抵抗，而COX-2(-/-)小鼠仍然易感。这些发现被异构体特异性的药物抑制所证实。缺乏mPGES-1(因此PGE(2))的小鼠正常发生关节炎，而对PGI(2)无反应的小鼠的关节炎病程显著减轻，证实了PGI(2)在该关节炎模型中的作用。这些发现挑战了以前关于COX亚型的不同“家务”和炎症功能的范式，并强调了通过COX-1合成的前列腺素类化合物，特别是PGI(2)，对炎症性关节炎的潜在致病作用。
Objective. Prostaglandins (PGs) are found in high levels in the synovial fluid of patients with rheumatoid arthritis, and nonsteroidal blockade of these bioactive lipids plays a role in patient care. The aim of this study was to explore the relative contribution of cyclooxygenase (COX) isoforms and PG species in the autoantibody-driven K/BxN serum-transfer arthritis.Methods. The prostanoid content of arthritic ankles was assessed in ankle homogenates, and the importance of this pathway was confirmed with pharmacologic blockade. The presence of COX isoforms was assessed by Western blotting and their functional contribution was compared using COX-1(-/-) and COX-2(-/-) mice as well as isoform-specific inhibitors. The relative importance of PGE(2) and PGI(2) (prostacyclin) was determined using mice deficient in microsomal PGE synthase 1 (mPGES-1) and in the receptors for PGI(2).Results. High levels of PGE(2) and 6-keto-PGF(1 alpha) (a stable metabolite of PGI(2)) were detected in arthritic joint tissues, correlating strongly with the intensity of synovitis. Pharmacologic inhibition of PG synthesis prevented arthritis and ameliorated active disease. While both COX isoforms were found in inflamed joint tissues, only COX-1 contributed substantially to clinical disease; COX-1(-/-) mice were fully resistant to disease, whereas COX-2(-/-) mice remained susceptible. These findings were confirmed by isoform-specific pharmacologic inhibition. Mice lacking mPGES-1 (and therefore PGE(2)) developed arthritis normally, whereas mice incapable of responding to PGI(2) exhibited a significantly attenuated arthritis course, confirming a role of PGI(2) in this arthritis model.Conclusion. These findings challenge previous paradigms of distinct "housekeeping" versus inflammatory functions of the COX isoforms and highlight the potential pathogenic contribution of prostanoids synthesized via COX-1, in particular PGI(2), to inflammatory arthritis.