title: 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.
authors.affiliation: Department of Dermatology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Fishelevich
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Papapit
authors.initials: P
authors.lastname: Tuchinda
authors.forename: Hannah
authors.initials: H
authors.lastname: Liu
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakazono
authors.forename: Antonella
authors.initials: A
authors.lastname: Tammaro
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Meng
authors.forename: Jim
authors.initials: J
authors.lastname: Lee
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Gaspari
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D000077271:Imiquimod; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051760:Xeroderma Pigmentosum Group A Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011740:Pyrimidine Dimers; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D000077271:Imiquimod