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J Invest Dermatol. 2014 Jun;134(6):1710-7. doi: 10.1038/jid.2013.530. Epub 2013 Dec 10.

Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism.

Author information

1
Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
2
1] Department of Dermatology, Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA [2] Veteran Affairs Medical Center, Birmingham, Alabama, USA [3] Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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.

PMID:
24326454
PMCID:
PMC4020975
DOI:
10.1038/jid.2013.530
[Indexed for MEDLINE]
Free PMC Article
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