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Photochem Photobiol. 2016 Nov;92(6):816-825. doi: 10.1111/php.12659. Epub 2016 Dec 8.

Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin.

Author information

1
The University of Arizona Cancer Center, Tucson, AZ.
2
Department of Medicine, The University of Arizona, Tucson, AZ.
3
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA.
4
Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, MN.
5
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
6
Department of Pharmacology, The University of Arizona, Tucson, AZ.

Abstract

Cutaneous exposure to solar ultraviolet (UV) radiation is a major causative factor in skin carcinogenesis, and improved molecular strategies for efficacious chemoprevention of nonmelanoma skin cancer (NMSC) are urgently needed. Toll-like receptor 4 (TLR4) signaling has been shown to drive skin inflammation, photoimmunosuppression, and chemical carcinogenesis. Here we have examined the feasibility of genetic and pharmacological antagonism targeting cutaneous TLR4 for the suppression of UV-induced NF-κB and AP-1 signaling in keratinocytes and mouse skin. Using immunohistochemical and proteomic microarray analysis of human skin, we demonstrate for the first time that a significant increase in expression of TLR4 occurs in keratinocytes during the progression from normal skin to actinic keratosis, also detectible during further progression to squamous cell carcinoma. Next, we demonstrate that siRNA-based genetic TLR4 inhibition blocks UV-induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid (TAK-242), a molecularly targeted clinical TLR4 antagonist, blocks UV-induced NF-κB and MAP kinase/AP-1 activity and cytokine expression (Il-6, Il-8, and Il-10) in cultured keratinocytes and in topically treated murine skin. Taken together, our data reveal that pharmacological TLR4 antagonism can suppress UV-induced cutaneous signaling, and future experiments will explore the potential of TLR4-directed strategies for prevention of NMSC.

PMID:
27859308
PMCID:
PMC5161657
DOI:
10.1111/php.12659
[Indexed for MEDLINE]
Free PMC Article

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