Department of Dermatology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA.
J Immunol. 2011 Aug 15;187(4):1664-73. doi: 10.4049/jimmunol.1100755. Epub 2011 Jul 15.
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.
咪喹莫特是一种 TLR7/8 激动剂，在治疗癌前皮肤病变和某些非黑色素瘤皮肤癌方面具有抗癌治疗效果。为了验证我们的假设，即咪喹莫特通过增强 DNA 修复作为其抗癌活性的一种机制，我们研究了骨髓细胞中的核苷酸切除修复基因。咪喹莫特增强了着色性干皮病（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 MyD88，因为来自 MyD88(-/-) 小鼠的骨髓细胞不会增加 XPA 基因表达，并且在 MyD88(+/+) 小鼠的骨髓细胞中观察到的 UVB 暴露后不会增强 MyD88(-/-)衍生的骨髓细胞的存活。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 UVL 暴露后 P388 和 XS52 中环丁烷嘧啶二聚体的解析。最后，在用 5%咪喹莫特乳膏局部处理小鼠皮肤后进行 UVL 照射，导致在两种野生型和 IL-12 基因靶向小鼠的局部淋巴结中，在 UVL 照射后 24 小时发现的环丁烷嘧啶二聚体阳性 APC 的数量减少。总的来说，这些数据支持 TLR7 激动剂（如咪喹莫特）增强骨髓细胞中 DNA 修复的观点。这种特性可能是其抗癌作用的重要机制，因为它可以保护皮肤 APC 免受 UVL 的有害影响。
