Biomechanical signals inhibit IKK activity to attenuate NF-κB transcription activity in inflamed Chondrocytes
Biomechanical signals inhibit IKK activity to attenuate NF-κB transcription activity in inflamed Chondrocytes
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DOI：
10.1002/art.22933
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发表时间：
2007-10-01
影响因子：
--
通讯作者：
Agarwal, Sudha
中科院分区：
文献类型：
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作者：
Dossumbekova, Anar;Anghelina, Mirela;Agarwal, Sudha
目的：虽然已知关节运动和锻炼形式的生物力学信号的作用对发炎关节有益，但关于其作用的细胞内机制的信息有限。本研究旨在探讨生物力学信号通过白细胞介素-1-β（IL-1 β）诱导的NF-κ B信号级联抑制关节软骨细胞中促炎基因诱导的细胞内机制。将原代大鼠关节软骨细胞暴露于周期性拉伸应变形式的生物力学信号，通过Western blot分析、实时聚合酶链反应和免疫荧光检测对NF-κ B信号级联的影响。循环拉伸应变迅速抑制IL-1 β诱导的NF-κ B核转位，但不能抑制IL-1 β诱导的丝氨酸276和丝氨酸536磷酸化，这两个位点分别是其转录和转录功效所必需的。上游事件的检查显示，周期性拉伸应变也抑制I κ B β和I κ B α的细胞质蛋白降解，以及抑制其基因转录。此外，循环拉伸应变诱导I κ B α的快速核转位，从而潜在地阻止NF κ B与DNA结合。环状拉伸应变抑制IL-1 β诱导的I kappa B降解可能是通过下调I kappa B激酶活性实现的。这些结果表明，由循环拉伸应变产生的信号作用于NF-B信号级联中的多个位点，以抑制IL-1 β诱导的促炎基因诱导。总的来说，这些发现提供了生物力学信号如何调节和减少炎症的见解，并强调了它们在增强软骨细胞抑制患病关节炎症的能力方面的潜力。
Objective: While the effects of biomechanical signals in the form of joint movement and exercise are known tob e beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examinie the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-beta (IL-1 beta)-induced NF-kappa B signaling cascade in articular chondrocytes.Methods. Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-kappa B signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence.Results. Cyclic tensile strain rapidly inhibited the IL-1 beta-induced nuclear translocation of NF-kappa B, but not its IL-1 beta-induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transciptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of I kappa B beta and I kappa B alpha, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of I kappa B alpha to potentially prevent NF kappa B binding to DNA. Furthermore, the inhibition of IL-1 beta-induced degradation of I kappa B by clyclic tensile strain was mediated by down-regulation of I kappa B kinase activity.Conclusion. These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-B signaling cascade to inhibit IL-1 beta-induced proinflammatory gene induction. Taken together, these findings provide insight into how biomechanical signals regulate and reduce inflammation, and underscore their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.