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

作者：Singh Anand; Koduru Bhargav; Carlisle Cameron; Akhter Hasina; Liu Rui Ming; Schroder Katrin; Brandes Ralf P; Ojcius David M^*

来源：Scientific Reports, 2017, 7(1): 14346.

DOI：10.1038/s41598-017-14574-8

Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Tolllike receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LPSinduced 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-alpha, and proliferating cell nuclear antigen (PCNA). Nox4 silencing suppressed LPS-induced TNF-alpha and PCNA increases in human cells. The LPS-induced TNF-alpha 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-kappa B and AP-1 pathways. Moreover, the effect of Nox4 depletion was time-dependent; following six weeks of repeated LPS stimulation in vivo, hepatic TNF-alpha 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.

• 出版日期2017-10-30