<i>Dlk1</i>Influences Differentiation and Function of<i>β</i>Lymphocytes

Raghunandan, Rama; Ruiz-Hidalgo, Marı́a José; Jia, Yan; Ettinger, Rachael; Rudikoff, Eva; Riggins, Patrick; Farnsworth, Richard L.; Tesfaye, Abeba; Laborda, Jorge; Bauer, Steven R.

doi:10.1089/scd.2007.0102

Cited by 76 publications

(77 citation statements)

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“…On the other hand, activation of B cells during the recognition of thymusdependent antigens needs the cooperation of T cells activated earlier. In this sense, our previous work revealed that Dlk1-deficient mice showed an increased primary T-dependent antibody response [31]. These results are consistent with an improved antigen presentation by macrophages and dendritic cells from Dlk1-null animals, which can be due, at least in part, to a greater expression of co-stimulatory molecules and cytokines implicated in T-cell differentiation.…”

Section: Discussionsupporting

confidence: 81%

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

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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...

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Section: Discussionsupporting

confidence: 81%

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

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“…As reported previously (24) and shown in Fig. 7A, Dlk1 2/2 embryos were smaller during development and postnatally (35).…”

Section: Loss Of Dlk1 Function Does Not Affect Bone Remodeling In Micesupporting

confidence: 88%

“…Dlk1-deficient (Dlk1 2/2 ) mice were obtained from J. Laborda (University of Castilla-La Mancha, Ciudad Real, Spain) (24). Osteoblast-specific Dlk1-overexpressing mice (expressing Dlk1 under collagen 3.6-kb promoter Col1-Dlk1) with high circulating levels of sDLK1 were generated by our group (13).…”

Section: Animalsmentioning

confidence: 99%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic b-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic b-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1 2/2 ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1 2/2 mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic b-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.A growing body of work indicates that bone is an endocrine organ that regulates glucose metabolism through, in part, the hormone osteocalcin (OCN). OCN signals in b-cells through its bona fide receptor Gprotein-coupled receptor (Gprc6a) to increase b-cell proliferation and insulin secretion and acts on peripheral tissues to increase energy expenditure (1-3). In turn, insulin signaling in osteoblasts (OBs) stimulates the activation of OCN by promoting its decarboxylation (Glu-OCN) through the bone resorption arm of bone remodeling (1,4). The physiological relevance of these findings have been supported through studies demonstrating skeleton as a site of insulin resistance in mice fed a high-fat diet (5). Moreover, patients with a dominant negative mutation in Gprc6a show evidence of glucose intolerance (3). In all likelihood, the Glu-OCN-insulin feed-forward loop must be under a negative regulation to protect from hypoglycemia. Soluble factors responsible for this regulation have not yet been identified despite the demonstrated ability of transcription factors activating transcription factor 4 (ATF4) and forkhead box protein O1 (FoxO1) to regulate glucose metabolism through a negative regulation of OCN bioavailability (6,7). Delta like-1 (DLK1), also known as preadipocyte factor-1 (Pref-1), is a transmembrane protein belonging to the Notch/serrate/delta family (8,9). The full ectodomain of DLK1 is proteolytically cleaved to generate a soluble active protein named fetal antigen-1 (FA1), which is secreted by endocrine cells of pancreas, ovary, Leydig cells of the testis, adrenal glands, and pituitary gland (10). DLK1 has

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“…The Dlk1 (Delta-like 1 homologue) gene is expressed from the paternal allele. It encodes a protein with homology to members of the Notch-Delta family of signaling molecules, which is important for mammalian development (5)(6)(7). 80 kilobases downstream of Dlk1, the Gtl2 (gene trap locus 2) promoter is active only on the maternally inherited chromosome (8,9).…”

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confidence: 99%

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

Braem

Recolin

Rancourt

et al. 2008

Journal of Biological Chemistry

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We previously showed that genomic imprinting regulates matrix attachment region activities at the mouse Igf2 (insulinlike growth factor 2) locus and that these activities are functionally linked to neighboring differentially methylated regions (DMRs). Here, we investigate the similarly structured Dlk1/Gtl2 imprinted domain and show that in the mouse liver, the G/Crich intergenic germ line-derived DMR, a sequence involved in domain-wide imprinting, is highly retained within the nuclear matrix fraction exclusively on the methylated paternal copy, reflecting its differential function on that chromosome. Therefore, not only "classical" A/T-rich matrix attachment region (MAR) sequences but also other important regulatory DNA elements (such as DMRs) can be recovered from genomic MAR assays following a high salt treatment. Interestingly, the recovery of one A/T-rich sequence (MAR4) from the "nuclear matrix" fraction is strongly correlated with gene expression. We show that this element possesses an intrinsic activity that favors transcription, and using chromosome conformation capture quantitative real time PCR assays, we demonstrate that the MAR4 interacts with the intergenic germ line-derived DMR specifically on the paternal allele but not with the Dlk1/Gtl2 promoters. Altogether, our findings shed a new light on gene regulation at this locus.Genomic imprinting is a parent-of-origin gene-silencing mechanism required for normal mammalian development. It involves germ line-specific epigenetic modifications acquired on restricted regions of the genome (imprinting control region or element) that control the imprinting of several genes often over several hundred kilobase pairs. Accumulating evidence indicates that monoallelic expression at mammalian imprinted loci largely results from allele-specific higher order chromatin structures that impair or favor gene expression. In this context, it becomes crucial to elucidate the genomic architecture associated with imprinted genes as well as to identify DNA sequences and factors involved in such higher order chromatin organization. In the present work, we examine the potential role of the so-called matrix attachment regions (MARs) 3 in imprinting and gene regulation. MARs have been operationally defined in "in vitro MAR assays" by their ability to "attach" to a purified nuclear matrix or scaffold. In that context, they appear as A/T-rich DNA sequences that may be involved in chromatin structure and gene expression (1). They are frequently associated with enhancers and promote chromatin accessibility and histone acetylation. Using a "genomic MAR" assay based on high salt treatment of purified nucleus preparations (2, 3), we previously showed that parental genomic imprinting controls MAR activities at the mouse Igf2 (insulin-like growth factor 2) locus. That work indicated that tissue-specific MARs and differentially methylated regions (DMRs) may act as bipartite elements controlling the long range activity of other regulatory elements such as enhancers (3), thus contributing t...

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Dlk1Influences Differentiation and Function ofβLymphocytes

Abstract: ABSTRACT

Cited by 76 publications

References 50 publications

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

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

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

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