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Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells.

Abstract
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.
AuthorsRita Fishelevich, Yuming Zhao, Papapit Tuchinda, Hannah Liu, Ayako Nakazono, Antonella Tammaro, Tzu-Ching Meng, Jim Lee, Anthony A Gaspari
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 4 Pg. 1664-73 (Aug 15 2011) ISSN: 1550-6606 [Electronic] United States
PMID21765012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Aminoquinolines
  • Antineoplastic Agents
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Pyrimidine Dimers
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Xeroderma Pigmentosum Group A Protein
  • Xpa protein, mouse
  • imiquimod
Topics
  • Aminoquinolines (pharmacology)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Bone Marrow Cells (immunology, metabolism)
  • Cell Line
  • DNA Damage (drug effects, immunology, radiation effects)
  • DNA Repair (drug effects, genetics, immunology, radiation effects)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects, genetics, immunology, radiation effects)
  • Membrane Glycoproteins (agonists, genetics, immunology, metabolism)
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 (genetics, immunology, metabolism)
  • Pyrimidine Dimers (genetics, immunology, metabolism)
  • Signal Transduction (drug effects, immunology, radiation effects)
  • Skin Neoplasms (drug therapy, genetics, immunology)
  • Toll-Like Receptor 7 (agonists, genetics, immunology, metabolism)
  • Ultraviolet Rays (adverse effects)
  • Xeroderma Pigmentosum Group A Protein (biosynthesis, genetics, immunology)

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