NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
| Autor: | David M. Ojcius, Cameron Carlisle, Hasina Akhter, Bhargav Koduru, Rui-Ming Liu, Anand Singh, Katrin Schröder, Ralf P. Brandes |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Lipopolysaccharide Inbred C57BL Mice chemistry.chemical_compound 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Toll-like receptor Tumor Multidisciplinary NADPH oxidase biology Liver Disease Liver Neoplasms NOX4 3. Good health Cell biology Liver NADPH Oxidase 4 030220 oncology & carcinogenesis cardiovascular system Medicine lipids (amino acids peptides and proteins) Tumor necrosis factor alpha medicine.symptom Signal transduction Signal Transduction Carcinoma Hepatocellular Science Inflammation Article Cell Line 03 medical and health sciences Cell Line Tumor medicine Animals Humans urogenital system Inflammatory and immune system Carcinoma NADPH Oxidases Hepatocellular Mice Inbred C57BL Toll-Like Receptor 4 030104 developmental biology chemistry Hepatocytes biology.protein TLR4 Digestive Diseases Reactive Oxygen Species |
| Zdroj: | Scientific Reports Scientific reports, vol 7, iss 1 Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-14574-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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