NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4

Abstract Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Toll-like receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LP...

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Autores principales:	Anand Singh, Bhargav Koduru, Cameron Carlisle, Hasina Akhter, Rui-Ming Liu, Katrin Schroder, Ralf P. Brandes, David M. Ojcius
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/14803d8c07644567bd54da6829b932b4
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spelling	oai:doaj.org-article:14803d8c07644567bd54da6829b932b42021-12-02T11:40:58ZNADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-410.1038/s41598-017-14574-82045-2322https://doaj.org/article/14803d8c07644567bd54da6829b932b42017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-14574-8https://doaj.org/toc/2045-2322Abstract Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Toll-like receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LPS-induced reactive oxygen species (ROS) production and modulate TLR responses, but whether these enzymes function in TLR4 responses of hepatocytes is unknown. In the present work, we examined the role of NADPH oxidase 4 (Nox4) in LPS-induced TLR4 responses in human hepatoma cells and wildtype and Nox4-deficient mice. We found that LPS increased expression of Nox4, TNF-α, and proliferating cell nuclear antigen (PCNA). Nox4 silencing suppressed LPS-induced TNF-α and PCNA increases in human cells. The LPS-induced TNF-α increases were MyD88-dependent, and were attenuated in primary hepatocytes isolated from Nox4-deficient mice. We found that Nox4 mediated LPS-TLR4 signaling in hepatocytes via NF-ĸB and AP-1 pathways. Moreover, the effect of Nox4 depletion was time-dependent; following six weeks of repeated LPS stimulation in vivo, hepatic TNF-α and PCNA responses subsided in Nox4-deficient mice compared with wildtype mice. Therefore, our data suggest that Nox4 mediates LPS-TLR4 signaling in human hepatoma cells and murine hepatocytes and may contribute to the ability of LPS to stimulate liver pathology.Anand SinghBhargav KoduruCameron CarlisleHasina AkhterRui-Ming LiuKatrin SchroderRalf P. BrandesDavid M. OjciusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anand Singh Bhargav Koduru Cameron Carlisle Hasina Akhter Rui-Ming Liu Katrin Schroder Ralf P. Brandes David M. Ojcius NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
description	Abstract Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Toll-like receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LPS-induced reactive oxygen species (ROS) production and modulate TLR responses, but whether these enzymes function in TLR4 responses of hepatocytes is unknown. In the present work, we examined the role of NADPH oxidase 4 (Nox4) in LPS-induced TLR4 responses in human hepatoma cells and wildtype and Nox4-deficient mice. We found that LPS increased expression of Nox4, TNF-α, and proliferating cell nuclear antigen (PCNA). Nox4 silencing suppressed LPS-induced TNF-α and PCNA increases in human cells. The LPS-induced TNF-α increases were MyD88-dependent, and were attenuated in primary hepatocytes isolated from Nox4-deficient mice. We found that Nox4 mediated LPS-TLR4 signaling in hepatocytes via NF-ĸB and AP-1 pathways. Moreover, the effect of Nox4 depletion was time-dependent; following six weeks of repeated LPS stimulation in vivo, hepatic TNF-α and PCNA responses subsided in Nox4-deficient mice compared with wildtype mice. Therefore, our data suggest that Nox4 mediates LPS-TLR4 signaling in human hepatoma cells and murine hepatocytes and may contribute to the ability of LPS to stimulate liver pathology.
format	article
author	Anand Singh Bhargav Koduru Cameron Carlisle Hasina Akhter Rui-Ming Liu Katrin Schroder Ralf P. Brandes David M. Ojcius
author_facet	Anand Singh Bhargav Koduru Cameron Carlisle Hasina Akhter Rui-Ming Liu Katrin Schroder Ralf P. Brandes David M. Ojcius
author_sort	Anand Singh
title	NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
title_short	NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
title_full	NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
title_fullStr	NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
title_full_unstemmed	NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
title_sort	nadph oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by toll-like receptor-4
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/14803d8c07644567bd54da6829b932b4
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NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4

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