Type IIA secretory phospholipase A2 up-regulates cyclooxygenase-2 and amplifies cytokine-mediated prostaglandin production in human rheumatoid synoviocytes
Type IIA secretory phospholipase A2 up-regulates cyclooxygenase-2 and amplifies cytokine-mediated prostaglandin production in human rheumatoid synoviocytes
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DOI：
10.4049/jimmunol.165.5.2790
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发表时间：
2000-09-01
影响因子：
4.4
通讯作者：
Scott, KF
中科院分区：
文献类型：
--
作者：
Bidgood, MJ;Jamal, OS;Scott, KF
人IIA型分泌型磷脂酶A（2）（sPLA（2）-IIA）与几种免疫介导的炎性疾病相关。我们已经评估了sPLA（2）-IIA对类风湿性关节炎（RA）患者的原代滑膜成纤维细胞中PC产生的影响。在RA患者滑液中发现的浓度下，外源性加入的sPLA（2）-IIA剂量依赖性地增加了培养的滑膜成纤维细胞的TNF-α刺激的PGE（2）产生。滑膜细胞中TNF-α刺激的PGE，产生的增强伴随着环氧合酶（考克斯）-2和cPLA（2）-α表达的增加。用选择性抑制剂NS-398阻断考克斯-2酶活性可阻止TNF-α刺激和sPLA（2）-IIA扩增的PGE（2）产生，而不影响考克斯-2蛋白的诱导。然而，sPLA（2）抑制剂LY 311727可阻断sPLA（2）-IIA诱导的PGE（2）产生和增强的考克斯-2表达。使用三标记免疫荧光显微镜的共定位研究表明，sPLA（2）-IIA和cPLA（2）-α与COS-2在来自RA患者的CD 14阳性滑膜巨噬细胞和滑膜组织成纤维细胞的离散群体中共表达。我们提出了一个模型，其中RA滑膜细胞增强的sPLA（2）-IIA表达通过超诱导考克斯-2上调TNF-α介导的PG产生。因此，sPLA（2）-IIA可能是RA中精氨酸介导的滑膜炎症的关键调节剂。
Human type IIA secretory phospholipase A(2) (sPLA(2)-IIA) is induced in association with several immune-mediated inflammatory conditions. We have evaluated the effect of sPLA(2)-IIA on PC production in primary synovial fibroblasts from patients with rheumatoid arthritis (RA), At concentrations found in the synovial fluid of RA patients, exogenously added sPLA(2)-IIA dose-dependently amplified TNF-alpha -stimulated PGE(2) production by cultured synovial fibroblasts. Enhancement of TNF-alpha -stimulated PGE, production in synovial cells was accompanied by increased expression of cyclooxygenase (COX)-2 and cytosolic phospholipase A(2) (cPLA(2))-alpha. Blockade of COX-2 enzyme activity with the selective inhibitor NS-398 prevented both TNF-alpha -stimulated and sPLA(2)-IIA-amplified PGE(2) production without affecting COX-2 protein induction. However, both sPLA(2)-IIA-anlplificd PGE(2) production and enhanced COX-2 expression were blocked by the sPLA(2) inhibitor LY311727, Colocalization studies using triple-labeling immunofluorescence microscopy showed that sPLA(2)-IIA and cPLA(2)-alpha are coexpressed with COS-2 in discrete populations of CD14-positive synovial macrophages and synovial tissue fibroblasts from RA patients, Based on these findings, we propose a model whereby the enhanced expression of sPLA(2)-IIA by RA synovial cells up-regulates TNF-alpha -mediated PG production via superinduction of COX-2, Therefore, sPLA(2)-IIA may be a critical modulator of cytokine-mediated synovial inflammation in RA.