title: DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR-activated murine macrophages.
abstract: Delta-like protein 1 (DLK1) is a noncanonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro-inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-β and other pro-inflammatory cytokines, including TNF-α, IL-12, and IL-23. The expression of key proteins involved in IFN-β signaling, such as IRF3, IRF7, IRF1, or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation.
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: González
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Ruiz-García
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Monsalve
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Laborda
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: María J M
authors.initials: MJ
authors.lastname: Díaz-Guerra
authors.affiliation: Facultad de Medicina, Centro Regional de Investigaciones Biomédicas (CRIB), Unidad de Biomedicina UCLM-CSIC, Albacete, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ruiz-Hidalgo
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D020298:U937 Cells
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D050835:Interferon Regulatory Factors; D053759:Interleukin-23; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C497594:Relb protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; D018664:Interleukin-12; D016899:Interferon-beta
keywords: Cytokine; DLK1; Inflammatory inhibitor; Macrophage; NOTCH signaling; TLR