Notch1 upregulates LPS-induced macrophage activation by increasing NF-kappaB activity.
Macrophages present different Notch receptors and ligands on their surface. Following macrophage activation by LPS or other TLR ligands, Notch1 expression is upregulated. We report here that Notch signaling increases both basal and LPS-induced NF-kappaB activation, favoring the expression of genes implicated in the inflammatory response, such as the cytokines TNF-alpha and IL-6, or enzymes, such as iNOS. Delta4 seems to be the most effective ligand to induce Notch activation and increasing NF-kappaB transcriptional activity in macrophages. We show that Notch1 signaling promotes NF-kappaB translocation to the nucleus and DNA binding by increasing both phosphorylation of the IkappaB kinase alpha/beta complex and the expression of some NF-kappaB family members. Treatment of macrophages with the gamma-secretase inhibitor DAPT, which prevents the cleavage and activation of Notch receptors, inhibits all these processes, diminishing NF-kappaB activity following LPS stimulation. Additionally, we show that the active intracellular Notch fragment can directly interact with TNF-alpha and iNOS promoters. Our results suggest that Notch signaling results in an amplification of the macrophage-dependent inflammatory response by enhancing NF-kappaB signaling.
Monsalve
Eva
E
Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Albacete, Spain.
Ruiz-García
Almudena
A
Baladrón
Victoriano
V
Ruiz-Hidalgo
María José
MJ
Sánchez-Solana
Beatriz
B
Rivero
Samuel
S
García-Ramírez
José J
JJ
Rubio
Antonio
A
Laborda
Jorge
J
Díaz-Guerra
María José M
MJ
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D051881:Receptor, Notch1; C064045:delta protein; D051550:I-kappa B Kinase; D053829:Amyloid Precursor Protein Secretases