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

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.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.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.Sepsis is a lethal infection-induced systemic inflammatory syndrome and organ dysfunction triggered by bacteria or bacterial products. Sepsis-related mortality is a leading cause of death and is increasing worldwide [1-5]. An overwhelming systemic inflammatory response is the most frequent pathological picture associated with sepsis and leads to fatal multiple organ failure [6,7]. Many basic and clinical studies have focused on targeting proinflammatory mediators implicated in the pathophysiology of sepsis. Unfortunately, most clinical trials so far have not led to an improved overall outcome for persons with this serious medical condition [6-11].Notch signaling is a highly conserved pathway involved in cell fate decisions, proliferation, and survival [1