Complex Formation of the Interferon (IFN) Consensus Sequence-binding Protein with IRF-1 Is Essential for Murine Macrophage IFN-γ-induced iNOS Gene Expression

Xiong, Huabao; Zhu, Chen; Li, Hongxing; Chen, Fanglin; Mayer, Lloyd; Ozato, Keiko; Unkeless, Jay C.; Plevy, Scott E.

doi:10.1074/jbc.m209583200

Cited by 62 publications

(66 citation statements)

References 56 publications

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“…On the other hand, it has been described that NOTCH signaling increases IRF8 translation through phosphorylation of eIF4E [10]. Both IRF7 and IRF8 activities are essential for sustained or delayed expression of various cytokines, such as TNF-α, IL-6, IL-12, IL-23, or IFN-β [27], and enzymes, such as iNOS [28]. The higher expression of these transcription factors could explain the increase of pro-inflammatory cytokines detected in the absence of 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

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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: 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

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“…Without IRF8, Tot2 cells remain undifferentiated and grow continuously. IRF8 interacts with partner proteins, PU.1 and IRF1, to regulate target gene expression (20)(21)(22). By interacting with PU.1, IRF8 can bind to the EICE (Ets͞IRF composite element) in vitro; interaction with IRF1 allows IRF8 to bind to the IFN-stimulated response element.…”

Section: Together Irf8 -Chromatin Interaction Is Dynamic In Live Macmentioning

confidence: 99%

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

Laricchia-Robbio

Tamura

Karpova

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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IFN regulatory factor (IRF) 8 is a transcription factor that directs macrophage differentiation. By fluorescence recovery after photobleaching, we visualized the movement of IRF8-GFP in differentiating macrophages. Recovery data fitted to mathematical models revealed two binding states for IRF8. The majority of IRF8 was highly mobile and transiently interacted with chromatin, whereas a small fraction of IRF8 bound to chromatin more stably. IRF8 mutants that did not stimulate macrophage differentiation showed a faster recovery, revealing little interaction with chromatin. A macrophage activation signal by IFN-␥͞LPS led to a global slowdown of IRF8 movement, leading to increased chromatin binding. In fibroblasts where IRF8 has no known function, WT IRF8 moved as fast as the mutants, indicating that IRF8 does not interact with chromatin in these cells. However, upon introduction of IRF8 binding partners, PU.1 and͞or IRF1, the mobility of IRF8 was markedly reduced, producing a more stably bound component. Together, IRF8 -chromatin interaction is dynamic in live macrophages and influenced by partner proteins and immunological stimuli.real-time mobility ͉ transcription factor ͉ fluorescence recovery after photobleaching G ene expression in immune cells is controlled by binding of transcription factors to chromatin targets. A classic view is that active transcription factors stably bind to the chromatinized promoter to drive transcription, a view mostly derived from biochemical studies in vitro. With the advent of live cell technologies, the views on the behavior of transcription factors are changing. Studies by fluorescence recovery after photobleaching (FRAP) of many nuclear proteins show that they are highly mobile and only transiently interact with chromatin (1, 2). Proteins showing rapid mobility include general transcription factors, chromatin modifiers, and DNA replication factors (3-9). Some DNA-specific transcription factors, such as nuclear hormone receptors, are also highly mobile in live nuclei (10-12). In addition, Stat1 (signal transducer and activator of transcription 1), a transcription factor that regulates IFN responses, is shown to be mobile before and after translocation into the nucleus (13), although E2F and retinoblastoma protein appear to be more stationary (14). In contrast, core histones, stable components of chromatin, are essentially immobile, showing little recovery after photobleaching (15). A consensus emerging from these studies is that FRAP recovery primarily reflects interactions of nuclear proteins with chromatin and the surrounding genomic DNA (hereafter referred to as chromatin) (16). Nevertheless, photobleaching technologies are still in their early phase of application, and mechanisms regulating FRAP mobility are not fully understood. FRAP mobility might reflect an intrinsic chromatin-binding property of a protein. However, the mobility may be influenced by other factors, such as soluble molecular constituents and structural components of the nucleus. In addition, most transcripti...

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“…Well known IFN-␥-regulated genes with a potentially negative impact on T-cell activation include iNOS (NO production), COX-2 (prostaglandin production), and gp91phox (subunit of the ROSproducing NADPH oxidase). [32][33][34] In addition, iNOS, in concert with arginase-1, has been reported as a major contributor to the production of T cell-suppressive RNOSs by MDSCs. 20 In an attempt to unravel the suppressive mechanism of the MDSC subfractions, specific inhibitors of each pathway were used in OVA-stimulated cultures ( Figure 5B).…”

Section: Figure 4 Both Mdsc Subfractions Have the Capacity To Supprementioning

confidence: 99%

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity

Movahedi

Guilliams

Bossche

et al. 2008

Blood

1,102

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Complex Formation of the Interferon (IFN) Consensus Sequence-binding Protein with IRF-1 Is Essential for Murine Macrophage IFN-γ-induced iNOS Gene Expression

Cited by 62 publications

References 56 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

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity

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