Differential regulation of cyclooxygenase‐2 and inducible nitric oxide synthase by 4‐hydroxynonenal in human osteoarthritic chondrocytes through ATF‐2/CREB‐1 transactivation and concomitant inhibition of NF‐κB signaling cascade
Differential regulation of cyclooxygenase‐2 and inducible nitric oxide synthase by 4‐hydroxynonenal in human osteoarthritic chondrocytes through ATF‐2/CREB‐1 transactivation and concomitant inhibition of NF‐κB signaling cascade
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DOI：
10.1002/jcb.21110
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发表时间：
2007-04
影响因子：
4
通讯作者：
F. Vaillancourt;B. Morquette;Q. Shi;H. Fahmi;P. Lavigne;J. D. Di Battista;J. Fernandes;M. Benderdour
中科院分区：
文献类型：
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作者：
F. Vaillancourt;B. Morquette;Q. Shi;H. Fahmi;P. Lavigne;J. D. Di Battista;J. Fernandes;M. Benderdour
4-羟基壬烯醛 (HNE) 是一种脂质过氧化终产物，在骨关节炎 (OA) 关节组织中大量产生，最近被确定为 OA 软骨中的有效分解代谢因子。在这项研究中，我们通过阐明 OA 软骨细胞中导致环氧合酶-2 (COX-2) 和诱导型一氧化氮合酶 (iNOS) 基因表达的信号级联，提供了 HNE 作为炎症介质的额外证据。 HNE 诱导 COX-2 蛋白和 mRNA 水平，并伴随前列腺素 E2 (PGE2) 产量的增加。相比之下，HNE 对基础 iNOS 表达或一氧化氮 (NO) 释放没有影响。然而，HNE 强烈抑制 IL-1β 诱导的 iNOS 或 NO 产生。瞬时转染实验表明，ATF/CRE 位点 (−58/−53) 对于 HNE 诱导的 COX-2 启动子激活至关重要，并且实际上 HNE 诱导 ATF-2 和 CREB-1 磷酸化以及 ATF/CRE 结合活性。 p38 MAPK 的过表达增强了 HNE 诱导的 ATF/CRE 荧光素酶报告质粒激活、COX-2 合成和启动子活性。 HNE 主要通过 NF-κB 位点 (-5,817/-5,808) 消除 IL-1β 诱导的 iNOS 表达和启动子活性，可能是通过抑制 IKKα 诱导的 IκBα 磷酸化和 NF-κB/p65 核转位。通过检查上游信号成分，我们发现 IKKα 通过 HNE/IKKα 加合物形成而失活。总而言之，这些发现说明了 HNE 在 OA 中 COX-2 和 iNOS 的调节中发挥的核心作用。醛通过 ATF/CRE 激活选择性诱导 COX-2 表达，并通过 IKKα 失活抑制 iNOS。 J.细胞。生物化学。 100: 1217–1231, 2007。© 2006 Wiley-Liss, Inc.
4‐hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues and was recently identified as a potent catabolic factor in OA cartilage. In this study, we provide additional evidence that HNE acts as an inflammatory mediator by elucidating the signaling cascades targeted in OA chondrocytes leading to cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) gene expression. HNE induced COX‐2 protein and mRNA levels with accompanying increases in prostaglandin E2 (PGE2) production. In contrast, HNE had no effect on basal iNOS expression or nitric oxide (NO) release. However, HNE strongly inhibited IL‐1β‐induced iNOS or NO production. Transient transfection experiments revealed that the ATF/CRE site (−58/−53) is essential for HNE‐induced COX‐2 promoter activation and indeed HNE induced ATF‐2 and CREB‐1 phosphorylation as well as ATF/CRE binding activity. Overexpression of p38 MAPK enhanced the HNE‐induced ATF/CRE luciferase reporter plasmid activation, COX‐2 synthesis and promoter activity. HNE abrogated IL‐1β‐induced iNOS expression and promoter activity mainly through NF‐κB site (−5,817/−5,808) possibly via suppression of IKKα‐induced IκBα phosphorylation and NF‐κB/p65 nuclear translocation. Upon examination of upstream signaling components, we found that IKKα was inactivated through HNE/IKKα adduct formation. Taken together, these findings illustrate the central role played by HNE in the regulation of COX‐2 and iNOS in OA. The aldehyde induced selectively COX‐2 expression via ATF/CRE activation and inhibited iNOS via IKKα inactivation. J. Cell. Biochem. 100: 1217–1231, 2007. © 2006 Wiley‐Liss, Inc.