Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway.
Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway.
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分解代谢细胞因子通过 NFкB 依赖性途径破坏生物钟和软骨中时钟控制基因的表达
DOI：
10.1016/j.joca.2015.02.020
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发表时间：
2015-11
影响因子：
7
通讯作者：
Meng QJ
中科院分区：
文献类型：
--
作者：
Guo B;Yang N;Borysiewicz E;Dudek M;Williams JL;Li J;Maywood ES;Adamson A;Hastings MH;Bateman JF;White MR;Boot-Handford RP;Meng QJ
确定分解代谢细胞因子（白细胞介素1（IL-1）和肿瘤坏死因子α（TNFα））如何影响软骨内生物钟机制和生物钟控制的分解代谢基因的表达，并确定将细胞因子与软骨细胞内分子钟联系起来的下游途径。从Cry 1-luc或PER 2：：LUC时钟报告基因小鼠中分离离体软骨外植体。通过生物发光光子计数实时监测时钟基因动态。通过qRT-PCR研究基因表达变化。使用功能性luc测定来研究SW-1353细胞中核心Clock/BMAL 1复合物的功能。采用NF B通路抑制剂和软骨荧光实时成像技术研究其机制。暴露于IL-1β严重破坏了软骨中的昼夜基因表达节律。这种作用被抗炎药地塞米松逆转，但不能被其他时钟同步剂逆转。由IL-1β介导的昼夜节律破坏伴随着内源性时钟基因和时钟控制的分解代谢途径的表达失调。从机制上讲，NF B信号传导参与了IL-1β对软骨时钟的影响，部分是通过对核心时钟/BMAL 1复合物的功能干扰。相反，TNFα对软骨中的昼夜节律和时钟基因表达的影响很小。在我们的实验系统（年轻健康小鼠软骨）中，我们证明IL-1β（而不是TNFα）消除了Cry 1-luc和PER 2：：LUC基因表达的昼夜节律。这些数据表明软骨细胞时钟的破坏是软骨对促炎细胞因子的分解代谢反应的一个新方面，并为慢性关节炎如何导致骨关节炎（OA）提供了另一种机制。
To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes. Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT-PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NFкB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms. Exposure to IL-1β severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1β was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFкB signalling was involved in the effect of IL-1β on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFα had little impact on the circadian rhythm and clock gene expression in cartilage. In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1β (but not TNFα) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA).