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Toll 样受体 4 缺乏通过核苷酸切除修复机制增强 UVR 诱导的皮肤 DNA 损伤的修复。

Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism.

机构信息

Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Veteran Affairs Medical Center, Birmingham, Alabama, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

出版信息

J Invest Dermatol. 2014 Jun;134(6):1710-1717. doi: 10.1038/jid.2013.530. Epub 2013 Dec 10.

DOI:10.1038/jid.2013.530
PMID:24326454
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4020975/
Abstract

UVB-induced DNA damage has a critical role in the development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4(-/-)) and TLR4-competent (TLR4(+/+)) mice were subjected to 90 mJ cm(-2) UVB radiation locally, DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) was repaired more efficiently in the skin and bone marrow-derived dendritic cells (BMDCs) of TLR4(-/-) mice in comparison to TLR4(+/+) mice. Expression of DNA repair gene XPA (xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDCs of TLR4(+/+) mice than TLR4(-/-) mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDCs from UV-irradiated TLR4(-/-) mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (P<0.05) than BMDCs from TLR4(+/+) mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDCs of TLR4(-/-) mice (before UVB exposure) inhibited repair of CPDs, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4(+/+) BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.

摘要

UVB 诱导的 DNA 损伤在光免疫抑制的发展中起着关键作用。本研究旨在确定 TLR4 是否调节 UVB 诱导的 DNA 损伤的修复。当 TLR4 基因敲除（TLR4(-/-)）和 TLR4 功能正常（TLR4(+/+)）的小鼠局部接受 90 mJ/cm(-2) 的 UVB 辐射时，TLR4(-/-) 小鼠的皮肤和骨髓来源树突状细胞（BMDCs）中的 DNA 损伤以环丁烷嘧啶二聚体（CPD）的形式修复得比 TLR4(+/+) 小鼠更有效。与 TLR4(-/-) 小鼠相比，TLR4(+/+) 小鼠皮肤和 BMDCs 中 DNA 修复基因 XPA（着色性干皮病互补组 A）的表达在 UVB 暴露后显著降低。与 UVB 暴露后的这些菌株中的细胞因子水平进行比较后发现，来自 UV 照射的 TLR4(-/-) 小鼠的 BMDCs 比 TLR4(+/+) 小鼠的 BMDCs 产生更多的白细胞介素（IL）-12 和 IL-23 细胞因子（P<0.05）。在 TLR4(-/-) 小鼠的 BMDC 中添加抗 IL-12 和抗 IL-23 抗体（在 UVB 暴露之前）抑制了 CPD 的修复，同时 XPA 表达也降低。TLR4 激动剂添加到 TLR4(+/+) BMDC 培养物中可降低 XPA 表达并抑制 CPD 修复。因此，抑制 TLR4 的策略可能为管理 UVB 诱导的皮肤 DNA 损伤和皮肤癌提供免疫预防和免疫治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/f022f4539a07/nihms546937f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/93e03827ce22/nihms546937f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/de6ffba8f026/nihms546937f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/8fbd05028a40/nihms546937f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/f022f4539a07/nihms546937f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/93e03827ce22/nihms546937f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/de6ffba8f026/nihms546937f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/8fbd05028a40/nihms546937f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a321/4020975/f022f4539a07/nihms546937f4.jpg

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