富马酸二甲酯在银屑病中靶向MSK1、RSK1、2和IKKα/β激酶并调节NF-κB /p65活化:富马酸二甲酯治疗前后对两例重度银屑病患者外周血单个核细胞的影响

IF 5.2 Q1 DERMATOLOGY Psoriasis (Auckland, N.Z.) Pub Date : 2020-03-31 eCollection Date: 2020-01-01 DOI:10.2147/PTT.S234151
Borbala Gesser, Mads K Rasmussen, Lars Iversen
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引用次数: 5

摘要

背景:富马酸二甲酯(DMF)对银屑病皮肤中参与免疫反应的不同细胞产生促炎蛋白具有抑制作用。最近的研究表明,DMF是p90核糖体S6激酶的变构共价抑制剂(rsk1,2),由x射线晶体学测定。DMF结合RSK2和密切相关的有丝分裂原和应激激活激酶1 (MSK1)中的特定半胱氨酸残基,抑制进一步的下游激活。目的:综述DMF对银屑病发病细胞中MSK1、RSK1、2激酶及下游转录因子NF-κB/p65和i -κB α活化的影响。我们还假设并研究了DMF治疗是否会抑制银屑病患者外周血单个核细胞(PBMCs)中MSK1, rsk1,2激酶的激活。方法:从重度银屑病患者DMF治疗前和治疗后90天纯化PBMCs。用大霉素、IL-1β或EGF刺激细胞10和20分钟。Western blotting分析MSK1、RSK1、2或NF-κB/p65、i -κB α磷酸化水平。结果:我们的病例研究表明,用DMF治疗可以抑制患者PBMCs中MSK1和rsk1,2激酶的激活。这支持DMF是银屑病患者在DMF治疗期间体内的活性代谢物。结论:促炎蛋白是通过MSK1和NF-κB/p65在(S276)处的活化而诱导的。细胞外信号调节激酶(ERK1/2)通过激活MSK1和rsk1,2激酶来控制细胞存活。P- rsk1,2激活P-κBα和NF-κB/p65 (S536)。NF-κB/p65在(S276)和(S536)位点的磷酸化控制不同的T细胞和树突状细胞功能。DMF对银屑病患者MSK1和rsk1,2激酶激活的抑制作用可减少多种免疫反应。
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Dimethyl Fumarate Targets MSK1, RSK1, 2 and IKKα/β Kinases and Regulates NF-κB /p65 Activation in Psoriasis: A Demonstration of the Effect on Peripheral Blood Mononuclear Cells, Drawn from Two Patients with Severe Psoriasis Before and After Treatment with Dimethyl Fumarate.

Background: Dimethyl fumarate (DMF) has an inhibitory effect on the production of pro-inflammatory proteins from different cells which participate in the immune reaction in psoriatic skin. Most recently it was shown that DMF is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases (RSK1, 2), determined by X-ray crystallography. DMF binds to a specific cysteine residue in RSK2 and in the closely related mitogen and stress-activated kinases 1 (MSK1) which inhibits further downstream activation.

Objectives: The aim of this study was to review the literature on the effects of DMF on activation of MSK1, RSK1, 2 kinases, and downstream transcription factors NF-κB/p65 and IκBα in cells contributing to the pathogenesis of psoriasis. We also hypothesized and studied if treatment with DMF would inhibit the activation of MSK1, RSK1, 2 kinases in peripheral blood mononuclear cells (PBMCs) in psoriatic patients.

Methods: PBMCs were purified from patients with severe psoriasis before and after 90 days of treatment with DMF. Cells were stimulated with anisomycin, IL-1β or EGF for 10 and 20 minutes. The levels of phosphorylation of MSK1, RSK1, 2 or NF-κB/p65, IκBα were analyzed by Western blotting.

Results: Our case study showed that treatment with DMF inhibited the activation of MSK1 and RSK1, 2 kinases in PBMCs in patients. This supports that DMF is the active metabolite in vivo in psoriatic patients during DMF treatment.

Conclusion: Pro-inflammatory proteins are induced through activation of MSK1 and NF-κB/p65 at (S276). The extracellular signal-regulated kinases (ERK1/2) control cell survival by activating both MSK1 and RSK1, 2 kinases. P-RSK1, 2 activates P-κBα and NF-κB/p65 at (S536). The phosphorylation of NF-κB/p65 at (S276) and (S536) controls different T cell and dendritic cell functions. DMF´s inhibitory effect on MSK1 and RSK1, 2 kinase activations reduces multiple immune reactions in psoriatic patients.

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