Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice

Ultraviolet (UV) irradiation of the skin is related to the development of skin cancer. UVB also causes DNA damage in the form of cyclobutane pyrimidine dimers (CPDs), which can result in stable mutations. Toll-like receptor 4 (TLR4), a component of innate immunity, plays a key role in cancer. Previo...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mohammad Asif Sherwani, Ahmed Abdelgawad, Minh Chung, Saad Ibrahim, Mualla Eraslan, Craig A. Elmets, Nabiha Yusuf
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ultraviolet radiation TLR4 inhibitor skin cancer DNA repair immune response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2616c362cabe4d4a846b7dc46902de41
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2616c362cabe4d4a846b7dc46902de41
record_format	dspace
spelling	oai:doaj.org-article:2616c362cabe4d4a846b7dc46902de412021-11-11T15:30:27ZToll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice10.3390/cancers132154062072-6694https://doaj.org/article/2616c362cabe4d4a846b7dc46902de412021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5406https://doaj.org/toc/2072-6694Ultraviolet (UV) irradiation of the skin is related to the development of skin cancer. UVB also causes DNA damage in the form of cyclobutane pyrimidine dimers (CPDs), which can result in stable mutations. Toll-like receptor 4 (TLR4), a component of innate immunity, plays a key role in cancer. Previous studies from our laboratory have observed that TLR4 deficiency resulted in the repair of UVB-induced DNA damage, inhibition of UVB-induced immune suppression, and carcinogenesis. In this study, we determined the efficacy of TLR4 antagonist TAK-242 in regulation of UVB-induced DNA damage, inflammation, and tumor development. Our results indicate that TAK-242 treatment increased the expression of xeroderma pigmentosum group A (XPA) mRNA, resulting in the repair of UVB-induced CPDs in skin of SKH-1 mice. Treatment with TAK-242 also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) in UVB-exposed skin of SKH-1 mice. Cutaneous carcinogenesis was significantly reduced in mice treated with TAK-242 in comparison to vehicle-treated mice. The proinflammatory cytokines IL-1β, IL-6, and TNF-α were also found to be significantly greater in vehicle-treated mice than TAK-242-treated mice. Finally, treatment with TAK-242 augmented anti-tumor immune responses in mice. Our data provide further evidence that activation of the TLR4 pathway promotes the development of UV-induced non-melanoma skin cancer mediated at least in part on its negative effects on DNA damage. Moreover, treatment with the TLR4 inhibitor TAK-242 may be effective for prevention of skin cancer.Mohammad Asif SherwaniAhmed AbdelgawadMinh ChungSaad IbrahimMualla EraslanCraig A. ElmetsNabiha YusufMDPI AGarticleultraviolet radiationTLR4 inhibitorskin cancerDNA repairimmune responseNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5406, p 5406 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ultraviolet radiation TLR4 inhibitor skin cancer DNA repair immune response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ultraviolet radiation TLR4 inhibitor skin cancer DNA repair immune response Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mohammad Asif Sherwani Ahmed Abdelgawad Minh Chung Saad Ibrahim Mualla Eraslan Craig A. Elmets Nabiha Yusuf Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
description	Ultraviolet (UV) irradiation of the skin is related to the development of skin cancer. UVB also causes DNA damage in the form of cyclobutane pyrimidine dimers (CPDs), which can result in stable mutations. Toll-like receptor 4 (TLR4), a component of innate immunity, plays a key role in cancer. Previous studies from our laboratory have observed that TLR4 deficiency resulted in the repair of UVB-induced DNA damage, inhibition of UVB-induced immune suppression, and carcinogenesis. In this study, we determined the efficacy of TLR4 antagonist TAK-242 in regulation of UVB-induced DNA damage, inflammation, and tumor development. Our results indicate that TAK-242 treatment increased the expression of xeroderma pigmentosum group A (XPA) mRNA, resulting in the repair of UVB-induced CPDs in skin of SKH-1 mice. Treatment with TAK-242 also inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) in UVB-exposed skin of SKH-1 mice. Cutaneous carcinogenesis was significantly reduced in mice treated with TAK-242 in comparison to vehicle-treated mice. The proinflammatory cytokines IL-1β, IL-6, and TNF-α were also found to be significantly greater in vehicle-treated mice than TAK-242-treated mice. Finally, treatment with TAK-242 augmented anti-tumor immune responses in mice. Our data provide further evidence that activation of the TLR4 pathway promotes the development of UV-induced non-melanoma skin cancer mediated at least in part on its negative effects on DNA damage. Moreover, treatment with the TLR4 inhibitor TAK-242 may be effective for prevention of skin cancer.
format	article
author	Mohammad Asif Sherwani Ahmed Abdelgawad Minh Chung Saad Ibrahim Mualla Eraslan Craig A. Elmets Nabiha Yusuf
author_facet	Mohammad Asif Sherwani Ahmed Abdelgawad Minh Chung Saad Ibrahim Mualla Eraslan Craig A. Elmets Nabiha Yusuf
author_sort	Mohammad Asif Sherwani
title	Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
title_short	Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
title_full	Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
title_fullStr	Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
title_full_unstemmed	Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice
title_sort	toll-like receptor-4 antagonist enhances the repair of ultraviolet radiation-induced dna damage and augments anti-tumor immune responses in mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2616c362cabe4d4a846b7dc46902de41
work_keys_str_mv	AT mohammadasifsherwani tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT ahmedabdelgawad tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT minhchung tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT saadibrahim tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT muallaeraslan tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT craigaelmets tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice AT nabihayusuf tolllikereceptor4antagonistenhancestherepairofultravioletradiationinduceddnadamageandaugmentsantitumorimmuneresponsesinmice
_version_	1718435228735766528

Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice

Ejemplares similares