The Journal of immunology (1950), 2011-08, Vol.187 (4), p.1664-1673
2011
Details
- Autor(en) / Beteiligte
- Titel
- Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells
- Ist Teil von
- The Journal of immunology (1950), 2011-08, Vol.187 (4), p.1664-1673
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-1767eISSN: 1550-6606DOI: 10.4049/jimmunol.1100755Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3150393
- Format
- –
- Schlagworte
- Aminoquinolines - pharmacology, Animals, Antineoplastic Agents - pharmacology, Bone Marrow Cells - immunology, Bone Marrow Cells - metabolism, Cell Line, DNA Damage - drug effects, DNA Damage - immunology, DNA Damage - radiation effects, DNA Repair - drug effects, DNA Repair - genetics, DNA Repair - immunology, DNA Repair - radiation effects, Female, Gene Expression Regulation, Neoplastic - drug effects, Gene Expression Regulation, Neoplastic - genetics, Gene Expression Regulation, Neoplastic - immunology, Gene Expression Regulation, Neoplastic - radiation effects, Imiquimod, Membrane Glycoproteins - agonists, Membrane Glycoproteins - genetics, Membrane Glycoproteins - immunology, Membrane Glycoproteins - metabolism, Mice, Mice, Knockout, Myeloid Differentiation Factor 88 - genetics, Myeloid Differentiation Factor 88 - immunology, Myeloid Differentiation Factor 88 - metabolism, Pyrimidine Dimers - genetics, Pyrimidine Dimers - immunology, Pyrimidine Dimers - metabolism, Signal Transduction - drug effects, Signal Transduction - immunology, Signal Transduction - radiation effects, Skin Neoplasms - drug therapy, Skin Neoplasms - genetics, Skin Neoplasms - immunology, Toll-Like Receptor 7 - agonists, Toll-Like Receptor 7 - genetics, Toll-Like Receptor 7 - immunology, Toll-Like Receptor 7 - metabolism, Ultraviolet Rays - adverse effects, Xeroderma Pigmentosum Group A Protein - biosynthesis, Xeroderma Pigmentosum Group A Protein - genetics, Xeroderma Pigmentosum Group A Protein - immunology