Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide

Mi Yeon Kim, Ji Hye Park, Jung Soon Mo, Eun Jung Ann, Seung Ok Han, Sang Hyun Baek, Kyoung Jin Kim, Suhn Young Im, Jeen Woo Park, Eui Ju Choi, Hee Sae Park

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


The Notch signaling pathway appears to perform an important function in inflammation. Here, we present evidence to suggest that lipopolysaccharide (LPS) suppresses Notch signaling via the direct modification of Notch by the nitration of tyrosine residues in macrophages. In the RAW264.7 macrophage cell line and in rat primary alveolar macrophages, LPS was found to inhibit Notch1 intracellular domain (Notch1-IC) transcription activity, which could then be rescued by treatment with N(G)-nitro-I-arginine, a nitric oxide synthase (NOS) inhibitor. Nitric oxide (NO), which was produced in cells that stably express endothelial NOS (eNOS) and brain NOS (bNOS), also induced the inhibition of Notch1 signaling. The NO-induced inhibition of Notch1 signaling remained unchanged after treatment with 1H-[1,2,4]oxadiazolo[4,3-alphalquinoxalin-1-one (ODQ), a guanylyl-cyclase inhibitor, and was not found to be mimicked by 8-bromo-cyclic GMP in the primary alveolar macrophages. With regards to the control of Notch signaling, NO appears to have a significant negative influence, via the nitration of Notch1-IC, on the binding that occurs between Notch1-IC and RBP-Jk, both in vitro and in vivo. By intrinsic fluorescence, we also determined that nitration could mediate conformational changes of Notch1-IC. The substitution of phenylalanine for tyrosine at residue 1905 in Notch1-IC abolished the nitration of Notch1-IC by LPS. Overall, our data suggest that an important relationship exists between LPS-mediated inflammation and the Notch1 signaling pathway, and that this relationship intimately involves the nitration of Notch1-IC tyrosine residues.

Original languageEnglish
Pages (from-to)1466-1476
Number of pages11
JournalJournal of Cell Science
Issue number9
Publication statusPublished - 2008 May 1


  • LPS
  • Nitric oxide
  • Notch

ASJC Scopus subject areas

  • Cell Biology


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