Direct regulation of interleukin-6 expression by Notch signaling in macrophages

Wongchana, Wipawee; Palaga, Tanapat

doi:10.1038/cmi.2011.36

Cited by 101 publications

(99 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The crosstalk between the Notch-1 and NF-kB pathways has been documented in macrophages and dendritic cells, 14,20,21 but unexplored in the intestinal epithelium, a cellular compartment known to fully rely on Notch-1 for its embryonic development. 7 Most studies have used either pharmacological g-secretase inhibitors or genetically modulated RBP-J (Recombination signal Binding Protein for Ig k J region) expression, a downstream regulator of Notch-1 activation.…”

Section: Discussionmentioning

confidence: 99%

Mouse and human Notch-1 regulate mucosal immune responses

et al. 2014

View full text Add to dashboard Cite

The Notch-1 signaling pathway is responsible for homeostatic tight junction expression in vitro, and promotes barrier function in vivo in the RAG1-adoptive transfer model of colitis. In this study, we sought to determine the role of colonic Notch-1 in the lymphoepithelial crosstalk in health and disease. We utilized in vivo and in vitro knockdown to target the expression of Notch-1. We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and upon inflammatory stimulus. Notch-1 expression modulates mucosal chemokine and cytokine secretion, and FoxP3 and effector T-cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium through crosstalk with the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathways that, in turn, elicits T-cell responses. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut. Our findings highlight an indispensable role for Notch-1-mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial proinflammatory responses.

show abstract

Section: Discussionmentioning

confidence: 99%

Mouse and human Notch-1 regulate mucosal immune responses

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The role of DLK1 as an inhibitor of the inflammatory response is also supported by the greater sensitivity of the Dlk1-deficient animals to LPS-induced endotoxic shock, and the increased expression of IFN-b1, TNF-a, Il-6, and Il-12p40 detected in the spleen of Dlk1-deficient mice and isolated macrophages. The expression of the cytokines modulated by DLK1 depends on NOTCH signaling, because it is inhibited in macrophages lacking RBPj [22,23] or in macrophages treated with γ-secretase inhibitors [3,24]. However, other cytokines induced after TLR activation, like IL-1β, are not modulated by NOTCH1 or DLK1.…”

Section: Discussionmentioning

confidence: 99%

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

González¹,

Ruiz-García²,

Monsalve³

et al. 2015

Eur J Immunol

View full text Add to dashboard Cite

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.Keywords: Cytokine r DLK1 r Inflammatory inhibitor r Macrophage r NOTCH signaling r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages are key cells in innate and adaptive immune response to pathogens. Toll-like receptors (TLR) recognize conserved microbial structures and induce the activation of macrophages, thus increasing their phagocytic and cytotoxic activities, and leading to the production of inflammatory cytokines, Correspondence: Dr. María J. Ruiz-Hidalgo and Dr. María J. M. Díaz-Guerra e-mail: Maria.RHidalgo@uclm.es; MariaJose.Martinez@uclm.es such as TNF-α and IL-1, and cytokines of the IL-6 and IL-12 families, which regulate T-cell differentiation [1].Macrophages display a remarkable plasticity and can change their functioning in response to environmental signals, which allows a fine-tuning of their activity to adapt to different situations. Unrestrained activation of TLR responses can lead to excessive inflammation and tissue damage and contribute to the pathogenesis of inflammatory disorders, such as septic shock. Multiple mechanisms are implicated in the control of macrophage activation, including inhibitory cytokines, transcriptional repressors, and epigenetic modifications [2,3].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2616 María J. González et al. Eur. J. Immunol. 2015. 45: 2615-2627 In this line, a critical role for NOTCH signaling in macrophage activation and polarization has been evidenced [4][5][6]. Ligand binding to the NOTCH receptors triggers a two-step proteolytic cleavage causing the release of the NOTCH intracellular doma...

show abstract

“…It is mainly produced by cells of the immune system, including T cells, B cells and macrophages [20,21]. It has also been reported that IL-6 is activated in the spinal cord, dorsal root ganglia, and Schwann cells in the spinal nerve roots following lumbar spinal stenosis, and that their expression is closely related to pain, and motor nerve dysfunction and degeneration [22].…”

Section: Introductionmentioning

confidence: 99%