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锌指转录因子作为一氧化氮介导的免疫抑制的分子靶点：对小鼠淋巴细胞中白细胞介素-2基因表达的抑制作用

Zinc finger transcription factors as molecular targets for nitric oxide-mediated immunosuppression: inhibition of IL-2 gene expression in murine lymphocytes.

作者信息

Berendji D, Kolb-Bachofen V, Zipfel P F, Skerka C, Carlberg C, Kröncke K D

机构信息

Research Group Immunobiology, MED_Heinrich_Heine University of Düsseldorf, Germany.

出版信息

Mol Med. 1999 Nov;5(11):721-30.

PMID:10656874
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2230482/
Abstract

BACKGROUND

Nitric oxide (NO) has frequently been shown to display immunosuppressive activities. We describe here a molecular mechanism contributing to this effect.

MATERIALS AND METHODS

Murine T cell lymphoma EL4-6.1 cells were activated with the physiological stimulus interleukin (IL)-1beta to express IL-2 mRNA in the presence or absence of subtoxic concentrations of the physiological spontaneous NO donor S-nitrosocysteine (SNOC). Subsequently, semiquantitative RT-PCR and gel shift assays with nuclear extracts were performed to analyze the effects of NO on IL-2 mRNA expression and on the activity of the dominant regulating transcription factors Sp1, EGR-1, and NFATc.

RESULTS

NO inhibits IL-1beta-induced IL-2 mRNA expression in EL4-6.1 cells. The suppressive activity of NO was concentration dependent and found to be completely reversible. Importantly, NO at the concentrations used induced neither apoptosis nor necrosis. Dominant regulation of IL-2 gene expression is known to reside in the zinc finger transcription factors Sp1 or EGR-1 and in the non-zinc finger protein NFAT. NO abrogates the DNA binding activities of recombinant Sp1 and EGR-1. More importantly, gel shift assays also showed a lack of DNA binding of native Sp1 derived from NO-treated nuclear extracts and that from NO-treated viable lymphocytes. This effect is selective, as the DNA binding activity of recombinant NFATc was not affected by NO.

CONCLUSION

Inactivation of zinc finger transcription factors by NO appears to be a molecular mechanism in the immunosuppressive activity of NO in mammals, thus contributing to NO-mediated inhibition of IL-2 gene expression after physiological stimuli. The exact understanding of the molecular mechanism leading to NO-mediated, fully reversible suppression of immune reactions may lead to use of this naturally occurring tool as an aid in inflammatory diseases.

摘要

背景

一氧化氮（NO）经常表现出免疫抑制活性。我们在此描述了一种导致这种效应的分子机制。

材料与方法

用生理刺激物白细胞介素（IL）-1β激活小鼠T细胞淋巴瘤EL4-6.1细胞，使其在存在或不存在亚毒性浓度的生理性自发NO供体S-亚硝基半胱氨酸（SNOC）的情况下表达IL-2 mRNA。随后，进行半定量RT-PCR和核提取物凝胶迁移分析，以分析NO对IL-2 mRNA表达以及主要调节转录因子Sp1、EGR-1和NFATc活性的影响。

结果

NO抑制EL4-6.1细胞中IL-1β诱导的IL-2 mRNA表达。NO的抑制活性呈浓度依赖性，且发现是完全可逆的。重要的是，所用浓度的NO既不诱导细胞凋亡也不诱导坏死。已知IL-2基因表达的主要调节作用存在于锌指转录因子Sp1或EGR-1以及非锌指蛋白NFAT中。NO消除了重组Sp1和EGR-1的DNA结合活性。更重要的是，凝胶迁移分析还显示，来自经NO处理的核提取物和经NO处理的活淋巴细胞的天然Sp1缺乏DNA结合能力。这种效应具有选择性，因为重组NFATc的DNA结合活性不受NO影响。

结论

NO使锌指转录因子失活似乎是哺乳动物中NO免疫抑制活性的一种分子机制，从而有助于在生理刺激后NO介导的对IL-2基因表达的抑制。对导致NO介导的、完全可逆的免疫反应抑制的分子机制的确切理解，可能会促使将这种天然存在的工具用于辅助治疗炎症性疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/82cfd7f16c8a/molmed00011-0026-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/c54347b20b31/molmed00011-0022-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/6afd29b26434/molmed00011-0023-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/4eb3c910709e/molmed00011-0023-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/3430e20eec45/molmed00011-0024-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/85abac76baa9/molmed00011-0025-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/82cfd7f16c8a/molmed00011-0026-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/c54347b20b31/molmed00011-0022-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/6afd29b26434/molmed00011-0023-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/4eb3c910709e/molmed00011-0023-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/3430e20eec45/molmed00011-0024-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/85abac76baa9/molmed00011-0025-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a1aa/2230482/82cfd7f16c8a/molmed00011-0026-a.jpg

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