Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide

Abstract

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-l-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-alpha]quinoxalin-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.

Notch-Dependent Repression of miR-155 in the Bone Marrow Niche Regulates Hematopoiesis in an NF-κB-Dependent Manner

“…Our discovery of the Notch/miR155/NF-κB/cytokines axis suggests the hypothesis that Notch signaling may contribute to hematopoietic homeostasis by regulating the level of the inflammatory state in the BM niche. In support of this idea, a recent report noted physiologic downregulation of Notch signaling in response to LPS (Kim et al, 2008a); furthermore epigenetic silencing of Notch in myeloid malignancies has been documented (Lobry et al, 2013). Thus, while transitory inhibition of Notch signaling in the BM microenvironment may trigger a physiologic inflammatory circuit characterized by miR-155/NF-κB/cytokine induction driving myeloid cell expansion in response to BM stress (such as infection or acute inflammation), continuous inhibition of Notch signaling due to persistence of inflammatory feed-back loops or/and epigenetic mechanisms, may contribute to the development or progression of a myeloproliferative disorder.…”

Notch Signal Suppresses Toll-like Receptor-triggered Inflammatory Responses in Macrophages by Inhibiting Extracellular Signal-regulated Kinase 1/2-mediated Nuclear Factor κB Activation

“…For example, LPS activates Notch signaling through a JNK-dependent pathway that subsequently regulates the inflammatory response (15). However, LPS was also reported to suppresses Notch signaling via nitric oxide in macrophages (16). A recent study demonstrated that Notch and TLR signaling pathways cooperate to activate the transcription of Notch target gene Hes1 and Hey and to increase the production of TLR-triggered cytokines such as TNF-␣, IL-6, and IL-12 (17).…”

Highly specific C–C bond cleavage induced FRET fluorescence for in vivo biological nitric oxide imaging

“…17 A significant enhancement of the fluorescence intensity was observed when the macrophages were incubated with DHPFQ and LPS (Fig. 2, middle).…”