Tumor Necrosis Factor-alpha utilizes MAPK/NFκB pathways to induce cholesterol-25 hydroxylase for amplifying pro-inflammatory response via 25-hydroxycholesterol-integrin-FAK pathway.
Tumor Necrosis Factor-alpha utilizes MAPK/NFκB pathways to induce cholesterol-25 hydroxylase for amplifying pro-inflammatory response via 25-hydroxycholesterol-integrin-FAK pathway.
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DOI：
10.1371/journal.pone.0257576
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Bose S
中科院分区：
文献类型：
--
作者：
Pokharel SM;Chiok K;Shil NK;Mohanty I;Bose S
夸大的炎症反应导致了各种炎症疾病的发病机制。肿瘤坏死因子- α (TNF)是一种多功能的促炎细胞因子，调节广泛的生理、生物和细胞过程。TNF诱导局灶黏附激酶（FAK）的各种活动，包括诱导促炎反应。FAK被TNF激活的机制尚不清楚，细胞表面整合素在调节TNF反应中的作用也尚未确定。在目前的研究中，我们已经确定了25-羟基胆固醇（25HC）作为一种可溶性细胞外脂质，可以放大TNF介导的先天免疫促炎反应。我们的研究结果表明，25HC-integrin-FAK通路放大并优化了tnf介导的促炎反应。TNF通过nf - κ b和MAPK途径诱导25HC生成酶胆固醇25-羟化酶（C25H）。具体来说，染色质免疫沉淀法鉴定了AP-1（激活蛋白-1）转录因子ATF2（激活转录因子2）在TNF刺激后与C25H启动子结合。此外，C25H、FAK和α5整合素表达的缺失，以及FAK和α5β1整合素分别被抑制剂和阻断抗体抑制，导致tnf介导的促炎反应减弱。因此，我们的研究表明，细胞外25HC将TNF通路与整合素- fak信号连接起来，以获得最佳的促炎活性，MAPK/ nfκ b - c25h -25HC-整合素- fak信号网络在放大TNF依赖性的促炎反应中发挥重要作用。因此，我们确定了在TNF介导的反应中，25HC是参与FAK激活的关键因子，并进一步证明了细胞表面整合素在正向调节TNF依赖的促炎反应中的作用。
Exaggerated inflammatory response results in pathogenesis of various inflammatory diseases. Tumor Necrosis Factor-alpha (TNF) is a multi-functional pro-inflammatory cytokine regulating a wide spectrum of physiological, biological, and cellular processes. TNF induces Focal Adhesion Kinase (FAK) for various activities including induction of pro-inflammatory response. The mechanism of FAK activation by TNF is unknown and the involvement of cell surface integrins in modulating TNF response has not been determined. In the current study, we have identified an oxysterol 25-hydroxycholesterol (25HC) as a soluble extracellular lipid amplifying TNF mediated innate immune pro-inflammatory response. Our results demonstrated that 25HC-integrin-FAK pathway amplifies and optimizes TNF-mediated pro-inflammatory response. 25HC generating enzyme cholesterol 25-hydroxylase (C25H) was induced by TNF via NFκB and MAPK pathways. Specifically, chromatin immunoprecipitation assay identified binding of AP-1 (Activator Protein-1) transcription factor ATF2 (Activating Transcription Factor 2) to the C25H promoter following TNF stimulation. Furthermore, loss of C25H, FAK and α5 integrin expression and inhibition of FAK and α5β1 integrin with inhibitor and blocking antibody, respectively, led to diminished TNF-mediated pro-inflammatory response. Thus, our studies show extracellular 25HC linking TNF pathway with integrin-FAK signaling for optimal pro-inflammatory activity and MAPK/NFκB-C25H-25HC-integrin-FAK signaling network playing an essential role to amplify TNF dependent pro-inflammatory response. Thus, we have identified 25HC as the key factor involved in FAK activation during TNF mediated response and further demonstrated a role of cell surface integrins in positively regulating TNF dependent pro-inflammatory response.
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DOI：
10.1038/nrrheum.2015.169
发表时间：
2016-01
期刊：
Nature reviews. Rheumatology
影响因子：
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作者：
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影响因子：
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发表时间：
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DOI：
10.1073/pnas.1404271111
发表时间：
2014-07-22
影响因子：
11.1
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