Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells
Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells
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DOI：
10.4049/jimmunol.1100755
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发表时间：
2011-08-15
影响因子：
4.4
通讯作者：
Gaspari, Anthony A.
中科院分区：
文献类型：
--
作者：
Fishelevich, Rita;Zhao, Yuming;Gaspari, Anthony A.
咪喹莫特是一种TLR 7/8激动剂，在治疗癌前皮肤病变和某些非黑色素瘤皮肤癌中具有抗癌治疗功效。为了验证我们的假设，即咪喹莫特增强DNA修复作为其抗癌活性的机制，在骨髓来源的细胞中研究了核苷酸切除修复基因。咪喹莫特增强着色性干皮病（XP）A和其他DNA修复基因的表达（定量实时PCR分析），并导致DNA修复酶XPA的核定位增加。这依赖于MyD 88，因为来自MyD 88（-/-）小鼠的骨髓衍生细胞不增加XPA基因表达，并且在UV B暴露后不增强MyD 88（-/-）衍生的骨髓衍生细胞的存活，如在来自MyD 88（+/+）小鼠的骨髓衍生细胞中观察到的。咪喹莫特还增强了紫外线（UVL）照射的基因表达构建体的DNA修复，并加速了P388和XS 52中UVL暴露后环丁烷嘧啶二聚体的分解。最后，在UVL照射前用5%咪喹莫特乳膏局部处理小鼠皮肤，导致野生型和IL-12基因靶向小鼠UVL照射后24小时在局部淋巴结中发现的环丁烷吡啶二聚体阳性APC的数量减少。总之，这些数据支持TLR 7激动剂如咪喹莫特增强骨髓来源细胞中的DNA修复的观点。这种特性可能是其抗癌作用的重要机制，因为它保护皮肤APC免受UVL的有害影响。免疫学杂志，2011，187：1664-1673。
Imiquimod is a TLR7/8 agonist that has anticancer therapeutic efficacy in the treatment of precancerous skin lesions and certain nonmelanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow-derived cells. Imiquimod enhanced the expression of xeroderma pigmentosum (XP) A and other DNA repair genes (quantitative real-time PCR analysis) and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow-derived cells from MyD88(-/-) mice did not increase XPA gene expression and did not enhance the survival of MyD88(-/-)-derived bone marrow-derived cells after UV B exposure as was observed in bone marrow-derived cells from MyD88(+/+) mice. Imiquimod also enhanced DNA repair of UV light (UVL)-irradiated gene expression constructs and accelerated the resolution of cyclobutane pyrimidine dimers after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer-positive APC that were found in local lymph nodes 24 h after UVL irradiation in both wild-type and IL-12 gene-targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow-derived cells. This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL. The Journal of Immunology, 2011, 187: 1664-1673.