title: Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin.
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.
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Janda
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Nichole B
authors.initials: NB
authors.lastname: Burkett
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Karen
authors.initials: K
authors.lastname: Blohm-Mangone
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Vivian
authors.initials: V
authors.lastname: Huang
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.|Department of Medicine, The University of Arizona, Tucson, AZ.
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.|Department of Medicine, The University of Arizona, Tucson, AZ.
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Calvert
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.|Department of Medicine, The University of Arizona, Tucson, AZ.
authors.forename: Janine
authors.initials: J
authors.lastname: Einspahr
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, MN.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, MN.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.|Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ.|Department of Pharmacology, The University of Arizona, Tucson, AZ.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Dickinson
mesh_terms: D000818:Animals; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D012867:Skin / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D016328:NF-kappa B; D011837:Radiation-Protective Agents; D013449:Sulfonamides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate