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

Jaroslav Janda, Nichole B. Burkett, Karen Blohm-Mangone, Vivian Huang, Clara N Curiel, David S Alberts, Emanuel F. Petricoin, Valerie S. Calvert, Janine G Einspahr, Zigang Dong, Ann M. Bode, Georg T Wondrak, Sally E Dickinson

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)816-825
Number of pages10
JournalPhotochemistry and Photobiology
Volume92
Issue number6
DOIs
StatePublished - Nov 1 2016

Fingerprint

Toll-Like Receptor 4
Transcription Factor AP-1
Keratinocytes
mice
Skin
Pharmacology
cancer
progressions
Skin Neoplasms
Carcinogenesis
Actinic Keratosis
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
ultraviolet radiation
Microarrays
Solar radiation
Chemoprevention
Ultraviolet radiation
Microarray Analysis
Small Interfering RNA
Proteomics

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Physical and Theoretical Chemistry

Cite this

Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin. / Janda, Jaroslav; Burkett, Nichole B.; Blohm-Mangone, Karen; Huang, Vivian; Curiel, Clara N; Alberts, David S; Petricoin, Emanuel F.; Calvert, Valerie S.; Einspahr, Janine G; Dong, Zigang; Bode, Ann M.; Wondrak, Georg T; Dickinson, Sally E.

In: Photochemistry and Photobiology, Vol. 92, No. 6, 01.11.2016, p. 816-825.

Research output: Contribution to journalArticle

Janda, Jaroslav ; Burkett, Nichole B. ; Blohm-Mangone, Karen ; Huang, Vivian ; Curiel, Clara N ; Alberts, David S ; Petricoin, Emanuel F. ; Calvert, Valerie S. ; Einspahr, Janine G ; Dong, Zigang ; Bode, Ann M. ; Wondrak, Georg T ; Dickinson, Sally E. / Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin. In: Photochemistry and Photobiology. 2016 ; Vol. 92, No. 6. pp. 816-825.
@article{07e0a6df5827407f9e9bcde76212ce0a,
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.",
author = "Jaroslav Janda and Burkett, {Nichole B.} and Karen Blohm-Mangone and Vivian Huang and Curiel, {Clara N} and Alberts, {David S} and Petricoin, {Emanuel F.} and Calvert, {Valerie S.} and Einspahr, {Janine G} and Zigang Dong and Bode, {Ann M.} and Wondrak, {Georg T} and Dickinson, {Sally E}",
year = "2016",
month = "11",
day = "1",
doi = "10.1111/php.12659",
language = "English (US)",
volume = "92",
pages = "816--825",
journal = "Photochemistry and Photobiology",
issn = "0031-8655",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Resatorvid-based Pharmacological Antagonism of Cutaneous TLR4 Blocks UV-induced NF-κB and AP-1 Signaling in Keratinocytes and Mouse Skin

AU - Janda, Jaroslav

AU - Burkett, Nichole B.

AU - Blohm-Mangone, Karen

AU - Huang, Vivian

AU - Curiel, Clara N

AU - Alberts, David S

AU - Petricoin, Emanuel F.

AU - Calvert, Valerie S.

AU - Einspahr, Janine G

AU - Dong, Zigang

AU - Bode, Ann M.

AU - Wondrak, Georg T

AU - Dickinson, Sally E

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85006240100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006240100&partnerID=8YFLogxK

U2 - 10.1111/php.12659

DO - 10.1111/php.12659

M3 - Article

C2 - 27859308

AN - SCOPUS:85006240100

VL - 92

SP - 816

EP - 825

JO - Photochemistry and Photobiology

JF - Photochemistry and Photobiology

SN - 0031-8655

IS - 6

ER -