| Abstract: |
Several signaling pathways, including the Notch pathway, can modulate TLR activation to achieve responses most appropriate for the environment. One mechanism of TLR-Notch cross-talk is TLR-induced expression of Notch ligands Jagged and Delta that feed back to engage Notch receptors on TLR-activated cells. In this study, we investigated mechanisms by which TLRs induce Notch ligand expression in primary macrophages. TLRs induced Jagged1 expression rapidly and independently of new protein synthesis. Jagged1 induction was augmented by IFN-γ, was partially dependent on canonical TLR-activated NF-κB and MAPK signaling pathways, and elevated Jagged1 expression augmented TLR-induced IL-6 production. Strikingly, TLR-induced Jagged1 expression was strongly dependent on the Notch master transcriptional regulator RBP-J and also on upstream components of the Notch pathway γ-secretase and Notch1 and Notch2 receptors. Thus, Jagged1 is an RBP-J target gene that is activated in a binary manner by TLR and Notch pathways. Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response. Copyright © 2010 by The American Association of Immunologists, Inc. |
| Keywords: |
signal transduction; mitogen activated protein kinase; controlled study; protein expression; intercellular signaling peptides and proteins; nonhuman; flow cytometry; animal cell; mouse; animal; metabolism; animals; mice; reverse transcription polymerase chain reaction; gene expression; animal experiment; animal model; membrane proteins; notch receptor; immunoglobulin enhancer binding protein; transfection; enzyme linked immunosorbent assay; mice, inbred c57bl; c57bl mouse; gene expression regulation; blotting, western; biosynthesis; immunology; regulatory mechanism; genetic transfection; gamma interferon; messenger rna; reverse transcriptase polymerase chain reaction; protein synthesis; rna, messenger; signal peptide; receptors, notch; membrane protein; western blotting; interleukin 6; cytokine production; immunomodulation; calcium binding protein; calcium-binding proteins; molecular interaction; enzyme-linked immunosorbent assay; macrophage; macrophages; cell separation; toll like receptor; notch1 receptor; gamma secretase; toll-like receptors; jagged1; notch2 receptor; serrate proteins; immunoglobulin j recombination signal sequence binding protein; rbpj protein, human; immunoglobulin j recombination signal sequence-binding protein
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