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Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response

Po-Nien Tsao1*, Shu-Chen Wei2, Miao-Tzu Huang3, Ming-Cheng Lee2, Hung-Chieh Chou1, Chien-Yi Chen1 and Wu-Shiun Hsieh1

Author Affiliations

1 Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

2 Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

3 Medical Research, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

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Journal of Biomedical Science 2011, 18:56 doi:10.1186/1423-0127-18-56

Published: 15 August 2011

Abstract

Background

Notch and TLR pathways were found to act cooperatively to activate Notch target genes and to increase the production of TLR-induced cytokines in macrophages. However, the mechanism of LPS-induced Notch activation and its role in sepsis still remains unclear.

Methods

We analyzed the expression patterns of Notch components in a LPS-stimulated murine macrophage cell line using real-time PCR and western blotting. The role of DAPT, a gamma-secretase inhibitor that is known to be a potent Notch inhibitor, in LPS-induced cytokine release and experimental sepsis in mice was also explored. Student's t-test was used to analyze the difference between the two groups.

Results

We found that Notch signaling was activated after LPS stimulation. The expression of Jagged 1, a Notch ligand, induced by LPS occurred in a JNK-dependent manner. In addition, Notch target genes were upregulated by early Notch-independent activation followed by delayed Notch-dependent activation after LPS stimulation. Disruption of Notch signaling by DAPT attenuated the LPS-induced inflammatory responses, including vascular endothelial growth factor (VEGF) and high-mobility group box chromosomal protein 1 (HMGB1), both in vitro and in vivo and partially improved experimental sepsis survival.

Conclusions

These findings support the existence of a synergistic effect of Notch signaling and the LPS pathway both in vitro and in vivo. Therefore, in the future Notch inhibitors may be utilized as adjunctive agents for the treatment of sepsis syndrome.