Loading…
DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages
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 activa...
Saved in:
Published in: | European journal of immunology 2015-09, Vol.45 (9), p.2615-2627 |
---|---|
Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | 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. |
---|---|
ISSN: | 0014-2980 1521-4141 |
DOI: | 10.1002/eji.201545514 |