Delphinidin inhibits IL-1β-induced activation of NF-κB by modulating the phosphorylation of IRAK-1Ser376 in human articular chondrocytes
Delphinidin inhibits IL-1β-induced activation of NF-κB by modulating the phosphorylation of IRAK-1Ser376 in human articular chondrocytes
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DOI：
10.1093/rheumatology/kes363
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发表时间：
2013-06-01
期刊：
影响因子：
5.5
通讯作者：
Haqqi, Tariq M.
中科院分区：
文献类型：
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作者：
Haseeb, Abdul;Chen, Dongxing;Haqqi, Tariq M.
目标。在骨性关节炎中，致炎细胞因子如IL-1β在受累关节中的表达增强。Delphinidin是一种在有色水果和蔬菜中发现的花青素，已被证明具有抗炎和抗氧化特性。在本研究中，我们检测了Delphinidin是否会抑制IL-1β诱导的人软骨细胞中核因子-kappaB的激活，并确定其作用机制。采用双抗体夹心法测定人骨关节炎软骨细胞中PGE(2)水平和核因子-kappaBp65的活性。免疫印迹法检测环氧合酶-2(COX-2)的蛋白表达和蛋白激酶的磷酸化。TaqMan法检测mRNAs的表达水平。Delphinidin抑制IL-1β诱导的人软骨细胞COX-2的表达和PGE(2)的产生。Delphinidin还抑制IL-1β介导的IL-1受体相关激酶-1(Ser376)的磷酸化、IKKα/β的磷酸化、IKKβ的表达、I-kappa Bα的降解以及核转录因子-kappa B/p65的激活和移位。在IL-1β处理的人软骨细胞中，未观察到转化生长因子-β激活的激酶1的磷酸化，但核因子-kappaB诱导的激酶(NIK)被磷酸化，并被Delphinidin阻断。这些数据证实了Delphinidin是一种新的抑制IL-1β通过抑制COX-2表达而产生软骨降解分子PGE(2)的抑制剂，并为其作用机制提供了新的见解。我们的结果还发现，在IL-1β诱导的人软骨细胞中，IRAK1(Ser376)磷酸化被Delphinidin抑制。鉴于IL-1β诱导的核因子-kappaB活化、COX-2表达和PGE(2)产生在骨性关节炎中所起的重要作用，我们的研究结果可能对开发预防/治疗骨性关节炎的新的治疗策略具有重要意义。
Objective. In OA, there is enhanced expression of pro-inflammatory cytokines such as IL-1 beta in the affected joint. Delphinidin, an anthocyanidin found in pigmented fruits and vegetables, has been shown to possess anti-inflammatory and antioxidant properties. In the present study we determined whether delphinidin would inhibit the IL-1 beta-induced activation of NF-kappa B in human chondrocytes and determined the mechanism of its action.Methods. PGE(2) levels and activation of NF-kappa B p65 in human OA chondrocytes were determined by ELISA-based assays. Protein expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of kinases was determined by western immunoblotting. Expression level of mRNAs was determined by TaqMan assays.Results. Delphinidin inhibited IL-1 beta-induced expression of COX-2 and production of PGE(2) in human chondrocytes. Delphinidin also inhibited IL-1 beta-mediated phosphorylation of IL-1 receptor-associated kinase-1(Ser376), phosphorylation of IKK alpha/beta, expression of IKK beta, degradation of I kappa B alpha, and activation and nuclear translocation of NF-kappa B/p65. Phosphorylation of TGF-beta-activated kinase 1 was not observed but NF-kappa B-inducing kinase (NIK) was phosphorylated and phosphorylation of NIK was blocked by delphinidin in IL-1 beta-treated human chondrocytes.Conclusion. These data identify delphinidin as a novel inhibitor of IL-1 beta-induced production of cartilage-degrading molecule PGE(2) via inhibition of COX-2 expression and provide new insight into the mechanism of its action. Our results also identify inhibition of IRAK1(Ser376) phosphorylation by delphinidin in IL-1 beta-induced activation of NF-kappa B in human chondrocytes. Given the important role played by IL-1 beta-induced NF-kappa B activation, COX-2 expression and PGE(2) production in OA, our results may have important implications for the development of novel therapeutic strategies for the prevention/treatment of OA.