Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis
Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis
复制标题
DOI：
10.1172/jci118717
复制
发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Gregory, SA
中科院分区：
文献类型：
--
作者：
Anderson, GD;Hauser, SD;Gregory, SA
由环氧合酶 (COX) 形成的前列腺素是关节炎炎症的重要介质。通过正常爪子和关节炎爪子中 COX-2 表达的表征以及 COX-2 活性的药理学抑制来评估诱导性 COX-2 酶对大鼠佐剂关节炎炎症的贡献。注射佐剂引起后足垫明显水肿，同时局部产生PGE(2)。 PG 的产生与受影响爪子中 COX-2 mRNA 和蛋白的上调有关。相反，COX-1 mRNA 水平不受佐剂注射的影响，发炎爪子中 TNF-α 和 IL-6 mRNA 以及血清中 IL-6 蛋白也增加。选择性 COX-2 抑制剂 SC-58125 的治疗性给药可迅速逆转爪水肿，并将爪组织中的 PGE(2) 水平降低至基线。有趣的是，用 COX-2 抑制剂治疗还降低了爪中 COX-2 mRNA 和蛋白的表达，血清 IL-6 和爪 IL-6 mRNA 水平也被 SC-58125 降低至接近正常水平。此外，抑制COX-2可减少炎症细胞浸润并减少滑膜炎症。值得注意的是，SC-58125 的抗炎作用与吲哚美辛观察到的作用没有区别。这些结果表明，COX-2 在与佐剂性关节炎相关的炎症中发挥着重要作用，并且 COX-2 衍生的 PG 上调炎症部位的 COX-2 和 IL-6 表达。
Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE(2). PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws, In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection, TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE(2) in paw tissue to baseline, Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw, Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin, These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.