title: Lipopolysaccharide-induced Notch signaling activation through JNK-dependent pathway regulates inflammatory response.
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.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. tsaopn@ntu.edu.tw
authors.forename: Po-Nien
authors.initials: PN
authors.lastname: Tsao
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Lee
authors.forename: Hung-Chieh
authors.initials: HC
authors.lastname: Chou
authors.forename: Chien-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Wu-Shiun
authors.initials: WS
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004151:Dipeptides / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008264:Macrophages; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051193:Toll-Like Receptors; D048670:MAP Kinase Kinase 4