Premium
Resatorvid‐based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV‐induced NF‐ κ B and AP‐1 Signaling in Keratinocytes and Mouse Skin
Author(s) -
Janda Jaroslav,
Burkett Nichole B.,
BlohmMangone Karen,
Huang Vivian,
CurielLewandrowski Clara,
Alberts David S.,
Petricoin Emanuel F.,
Calvert Valerie S.,
Einspahr Janine,
Dong Zigang,
Bode Ann M.,
Wondrak Georg T.,
Dickinson Sally E.
Publication year - 2016
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/php.12659
Subject(s) - carcinogenesis , skin cancer , cancer research , keratinocyte , signal transduction , actinic keratosis , nf κb , inflammation , tlr4 , imiquimod , medicine , chemistry , biology , pharmacology , immunology , cancer , cell culture , pathology , microbiology and biotechnology , basal cell , genetics
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 ( TLR 4) 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 TLR 4 for the suppression of UV ‐induced NF ‐ κ B 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 TLR 4 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 TLR 4 inhibition blocks UV ‐induced stress signaling in cultured keratinocytes. Importantly, we observed that resatorvid ( TAK ‐242), a molecularly targeted clinical TLR 4 antagonist, blocks UV ‐induced NF ‐ κ B 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 TLR 4 antagonism can suppress UV ‐induced cutaneous signaling, and future experiments will explore the potential of TLR 4‐directed strategies for prevention of NMSC .