Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways.
Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways.
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DOI：
10.1002/1529-0131(199904)42:4
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发表时间：
1999-04
影响因子：
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通讯作者：
Nada Alaaeddine;J. Battista;J. Pelletier;K. Kiansa;Cloutier Jm;J. Martel-Pelletier
中科院分区：
文献类型：
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作者：
Nada Alaaeddine;J. Battista;J. Pelletier;K. Kiansa;Cloutier Jm;J. Martel-Pelletier
目的探讨白细胞介素4（IL-4）、IL-10和IL-13对肿瘤坏死因子α（TNF α）诱导的人骨关节炎（OA）滑膜成纤维细胞释放前列腺素E2（PGE 2）的影响。方法培养人OA滑膜成纤维细胞，观察IL-4、IL-10和IL-13对TNF α与TNF受体（TNFR）、可溶性TNFR（sTNFR）、胞浆磷脂酶A2（cPLA 2）和环氧合酶2（考克斯-2）的结合以及转录因子核因子κ B（NF κ B）结合活性的影响。（NF-κ B）、CCAAT增强子结合蛋白（C/EBP）、激活蛋白2（AP-2）和环AMP反应元件结合蛋白（CREB）。结果5 ng/ml的IL-4、IL-10和IL-13显著降低TNF α诱导的PGE 2释放约90%（P < 0.0001）。IL-4使TNF α诱导的TNFR水平上调47%（P < 0.06），IL-10使其下调71%（P < 0.02），IL-13无影响。尽管未达到统计学显著性，但所有3种细胞因子均上调sTNFR-55的基础水平。IL-4和IL-10虽然不改变sTNFR-75的基础水平，但显著增加了TNF α刺激的sTNFR-75的释放。IL-4、IL-10和IL-13降低TNF α诱导的考克斯-2水平，IL-4和IL-10降低cPLA 2水平。IL-4对TNF-α上调NF-κ B没有影响，而IL-10和IL-13在最高浓度（5 ng/ml）时略有降低。IL-4和IL-13以剂量依赖性方式降低TNF α诱导的C/EBP积累，而IL-10上调其基础水平。AP-2和CREB不被TNF α诱导。结论这些细胞因子通过不同水平的TNF α依赖性信号级联反应逆转TNF α诱导的OA滑膜成纤维细胞释放PGE 2。这些数据揭示了这些细胞因子减少炎症过程的机制。
OBJECTIVE To investigate the effects of the antiinflammatory cytokines interleukin-4 (IL-4), IL-10, and IL-13 on tumor necrosis factor alpha (TNFalpha)-induced prostaglandin E2 (PGE2) release in the cellular signaling cascade on human osteoarthritis (OA) synovial fibroblasts. METHODS Human OA synovial fibroblasts were cultured to explore the impact of IL-4, IL-10, and IL-13 on TNFalpha binding to TNF receptors (TNFR), soluble TNFR (sTNFR), cytoplasmic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX-2) production, and on the binding activity of the transcription factors nuclear factor kappaB (NF-kappaB), CCAAT-enhancer binding protein (C/EBP), activator protein 2 (AP-2), and cyclic AMP response element-binding protein (CREB). RESULTS IL-4, IL-10, and IL-13 at 5 ng/ml dramatically reduced TNFalpha-induced PGE2 release by approximately 90% (P < 0.0001). IL-4 up-regulated the level of TNFalpha-induced TNFR by 47% (P < 0.06), while IL-10 down-regulated it by 71% (P < 0.02); IL-13 had no effect. Although statistical significance was not reached, all 3 cytokines up-regulated the basal level of sTNFR-55. IL-4 and IL-10, while not altering the basal level of sTNFR-75, significantly increased the TNFalpha-stimulated release of sTNFR-75. IL-4, IL-10, and IL-13 reduced the TNFalpha-induced COX-2 level, and IL-4 and IL-10 reduced the cPLA2 level. IL-4 had no effect on TNFalpha up-regulation of NF-kappaB, and a slight decrease was noted with IL-10 and IL-13 at the highest concentration used (5 ng/ml). IL-4 and IL-13 decreased the TNFa-induced C/EBP accumulation in a dose-dependent manner, while IL-10 up-regulated its basal level. AP-2 and CREB were not induced by TNFalpha. CONCLUSION The results indicate that these antiinflammatory cytokines reversed the TNFalpha-induced release of PGE2 by OA synovial fibroblasts, by acting at various levels of the TNFa-dependent signaling cascade. These data shed new light on the mechanisms by which these cytokines reduce inflammatory processes.