肽IDR-1002通过抑制IκBα降解来抑制NF-κB核转运，并激活脂多糖刺激的巨噬细胞中依赖于p38 / ERK1 / 2-MSK1的CREB磷酸化。,Frontiers in Immunology

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肽IDR-1002通过抑制IκBα降解来抑制NF-κB核转运，并激活脂多糖刺激的巨噬细胞中依赖于p38 / ERK1 / 2-MSK1的CREB磷酸化。
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2016-12-10 , DOI: 10.3389/fimmu.2016.00533
Alejandro Huante-Mendoza ₁ , Octavio Silva-García ₁ , Javier Oviedo-Boyso ₁ , Robert E W Hancock ₂ , Víctor M Baizabal-Aguirre ₁

Affiliation

炎症反应是先天免疫系统的关键分子防御机制，该机制介导消除致病细菌。消除病原体后，必须完成受损组织的修复和体内平衡的重建。天生的防御调节剂（IDR）是模仿天然宿主防御肽的短阳离子肽，可通过增强免疫系统的活性，同时控制炎症反应，有效消除病原体。尽管已经报道了不同的IDR作为炎症调节剂的作用，但是对于由这种类型的肽调节的信号传导分子只有有限的研究。本研究调查了IDR-1002对核因子κB（NF-κB）和cAMP反应元件结合蛋白（CREB）转录因子的影响，这些因子分别引发和控制巨噬细胞的炎症。我们发现在IDR-1002预孵育然后再用脂多糖（LPS）刺激的巨噬细胞中，TNF-α和COX-2的表达，IκBα磷酸化和NF-κB核易位受到强烈抑制。IDR-1002还通过激活p38 / ERK1 / 2-MSK1信号通路增加了Ser133处的CREB磷酸化，而没有检测到涉及的细胞因子IL-4，IL-10和IL-13的表达，从而抑制了炎症或其他激活作用。已知NF-κB和CREB的转录激活需要与转录共激活因子CREB结合蛋白（CBP）相互作用。为了测试CBP-NF-κB和CBP-CREB复合物的形成，我们进行了免疫共沉淀试验。这些试验表明，IDR-1002抑制了LPS刺激的巨噬细胞中CBP与NF-κB的相互作用，这可能解释了TNF-α和COX-2表达的抑制。此外，IDR-1002刺激的巨噬细胞中的CBP和CREB之间的复合物也被抑制，这也许可以解释为什么IDR-1002即使诱导了IL-4，IL-10和IL-13的表达也不导致IL-4，IL-10和IL-13的表达。磷酸-CREB相对丰度增加。总之，我们的结果表明IDR-1002具有双重作用。一方面，它通过涉及抑制IκBα磷酸化的机制来抑制NF-κB核易位，另一方面，它激活了蛋白激酶信号传导级联反应，使CREB磷酸化，从而选择性地影响细胞因子基因的表达。根据这些结果，我们认为IDR-1002可能是控制炎症的潜在良好生物药物候选物。

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Peptide IDR-1002 Inhibits NF-κB Nuclear Translocation by Inhibition of IκBα Degradation and Activates p38/ERK1/2-MSK1-Dependent CREB Phosphorylation in Macrophages Stimulated with Lipopolysaccharide.

The inflammatory response is a critical molecular defense mechanism of the innate immune system that mediates the elimination of disease-causing bacteria. Repair of the damaged tissue, and the reestablishment of homeostasis, must be accomplished after elimination of the pathogen. The innate defense regulators (IDRs) are short cationic peptides that mimic natural host defense peptides and are effective in eliminating pathogens by enhancing the activity of the immune system while controlling the inflammatory response. Although the role of different IDRs as modulators of inflammation has been reported, there have been only limited studies of the signaling molecules regulated by this type of peptide. The present study investigated the effect of IDR-1002 on nuclear factor κB (NF-κB) and cAMP-response element-binding protein (CREB) transcription factors that are responsible for triggering and controlling inflammation, respectively, in macrophages. We found that TNF-α and COX-2 expression, IκBα phosphorylation, and NF-κB nuclear translocation were strongly inhibited in macrophages pre-incubated with IDR-1002 and then stimulated with lipopolysaccharide (LPS). IDR-1002 also increased CREB phosphorylation at Ser133 via activation of the p38/ERK1/2-MSK1 signaling pathways without detectable expression of the cytokines IL-4, IL-10, and IL-13 involved is suppressing inflammation or alternative activation. Transcriptional activation of NF-κB and CREB is known to require interaction with the transcriptional coactivator CREB-binding protein (CBP). To test for CBP-NF-κB and CBP-CREB complex formation, we performed co-immunoprecipitation assays. These assays showed that IDR-1002 inhibited the interaction between CBP and NF-κB in macrophages stimulated with LPS, which might explain the inhibition of TNF-α and COX-2 expression. Furthermore, the complex between CBP and CREB in macrophages stimulated with IDR-1002 was also inhibited, which might explain why IDR-1002 did not lead to expression of IL-4, IL-10, and IL-13, even though it induced an increase in phospho-CREB relative abundance. In conclusion, our results indicated that IDR-1002 has a dual effect. On one hand, it inhibited NF-κB nuclear translocation through a mechanism that involved inhibition of IκBα phosphorylation, and on the other, it activated a protein kinase signaling cascade that phosphorylated CREB to selectively influence cytokine gene expression. Based on these results, we think IDR-1002 could be a potential good biopharmaceutical candidate to control inflammation.

更新日期：2019-11-01

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