title: Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism.
abstract: UVB-induced DNA damage has a critical role in the development of photoimmunosuppression. The purpose of this study was to determine whether repair of UVB-induced DNA damage is regulated by Toll-like receptor-4 (TLR4). When TLR4 gene knockout (TLR4(-/-)) and TLR4-competent (TLR4(+/+)) mice were subjected to 90 mJ cm(-2) UVB radiation locally, DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) was repaired more efficiently in the skin and bone marrow-derived dendritic cells (BMDCs) of TLR4(-/-) mice in comparison to TLR4(+/+) mice. Expression of DNA repair gene XPA (xeroderma pigmentosum complementation group A) was significantly lower in skin and BMDCs of TLR4(+/+) mice than TLR4(-/-) mice after UVB exposure. When cytokine levels were compared in these strains after UVB exposure, BMDCs from UV-irradiated TLR4(-/-) mice produced significantly more interleukin (IL)-12 and IL-23 cytokines (P<0.05) than BMDCs from TLR4(+/+) mice. Addition of anti-IL-12 and anti-IL-23 antibodies to BMDCs of TLR4(-/-) mice (before UVB exposure) inhibited repair of CPDs, with a concomitant decrease in XPA expression. Addition of TLR4 agonist to TLR4(+/+) BMDC cultures decreased XPA expression and inhibited CPD repair. Thus, strategies to inhibit TLR4 may allow for immunopreventive and immunotherapeutic approaches for managing UVB-induced cutaneous DNA damage and skin cancer.
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Israr
authors: I
authors: Ahmad
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Eva
authors: E
authors: Simanyi
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Purushotham
authors: P
authors: Guroji
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Iman A
authors: IA
authors: Tamimi
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Hillary J
authors: HJ
authors: delaRosa
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Anusuiya
authors: A
authors: Nagar
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Priyamvada
authors: P
authors: Nagar
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Veteran Affairs Medical Center, Birmingham, Alabama, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Santosh K
authors: SK
authors: Katiyar
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Veteran Affairs Medical Center, Birmingham, Alabama, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Craig A
authors: CA
authors: Elmets
authors: Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; Veteran Affairs Medical Center, Birmingham, Alabama, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: nabiha@uab.edu.
authors: Nabiha
authors: N
authors: Yusuf
mesh_terms: D000483:Alleles; D000818:Animals; D000938:Antigen-Presenting Cells; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D007165:Immunosuppression Therapy; D018664:Interleukin-12 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011740:Pyrimidine Dimers / Q000737:chemistry; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D053759:Interleukin-23; D011740:Pyrimidine Dimers; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051760:Xeroderma Pigmentosum Group A Protein; D018664:Interleukin-12