TGF-β 介导的抑制单核细胞 IL-12A 基因表达的信号通路

IF 3.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tetiana Hourani , Mahtab Eivazitork , Thivya Balendran , Kevin MC. Lee , John A. Hamilton , Hong-Jian Zhu , Josephine Iaria , Andrew P. Morokoff , Rodney B. Luwor , Adrian A. Achuthan
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引用次数: 0

摘要

转化生长因子-β(TGF-β)是一种多效细胞因子,对多种生物过程至关重要,包括对炎症和免疫反应的调节。TGF-β 的重要功能之一是抑制促炎细胞因子白细胞介素-12(IL-12),而白细胞介素-12 对抗肿瘤反应至关重要。尽管对 IL-12 的 IL-12p40 亚基(由 IL-12B 基因编码)的调控已有广泛研究,但对 IL-12p35(由 IL-12A 基因编码)亚基调控的了解相对有限。本研究探讨了 TGF-β 激活的信号通路对 THP-1 单核细胞中 IL-12A 的分子调控。我们的研究发现了 TGF-β 对 IL-12A 基因表达的复杂调控,其中涉及多种细胞信号通路,如 Smad2/3、NF-κB、p38 和 JNK1/2。药物抑制 NF-κB 信号传导会降低 IL-12A 的表达,而通过过表达 Smad7 来阻断 Smad2/3 信号传导途径,并用药物抑制剂 SP600125 来抑制 JNK1/2 信号传导,则会增加 IL-12A 的表达。所阐明的调控IL-12A基因表达的信号通路有可能为提高肿瘤微环境中的IL-12水平提供新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes

Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.

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来源期刊
Molecular immunology
Molecular immunology 医学-免疫学
CiteScore
6.90
自引率
2.80%
发文量
324
审稿时长
50 days
期刊介绍: Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.
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