Phosphorylation of IRF8 in a pre-associated complex with Spi-1/PU.1 and non-phosphorylated Stat1 is critical for LPS induction of the IL1B gene

Unlu, Sebnem; Kumar, Arvind; Waterman, Wayne R.; Tsukada, Junichi; Wang, Kent Z.Q.; Galson, Deborah L.; Auron, Philip E.

doi:10.1016/j.molimm.2007.02.016

Cited by 44 publications

(48 citation statements)

References 61 publications

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“…Previous studies revealed that IRF8 in conjunction with IRF-1 and IRF-2 negatively regulated some interferon-inducible gene via binding to interferon-stimulated response element, [41][42][43] whereas IRF8, together with PU.1, stimulated the activity of promoters harboring Ets-IRF composite element. 42,[44][45][46][47][48] It is conceivable to speculate that one mode of IRF8 action could be to suppress the expression of a cohort of neutrophilspecific genes and, at the same time, activate a group of macrophagespecific genes via interaction with different partners. This postulation correlates with the findings that macrophage formation requires high PU.1 activity in mammalian culture cells 49 and zebrafish (H.L., Z.L., unpublished data, January 2010), and forced expression of Irf8 alone in pu.1 knockdown embryos is insufficient to restore macrophage development ( Figure 6H-P).…”

Section: Discussionmentioning

confidence: 99%

Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis

Jin

et al. 2011

Blood

146

170

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IntroductionMyeloid cells or phagocytes are a subtype of leukocytes that play essential roles in the host defense, embryogenesis, organogenesis, and tissue regeneration. [1][2][3] In vertebrates, myeloid cells are classified into 2 major lineages: polymorphonuclear and mononuclear lineages, which acquire different morphologies during development and exert overlapping but distinctive biologic functions. Polymorphonuclear phagocytes consist of neutrophils, eosinophils, basophils, and mast cells. They are the key effectors of inflammatory response on pathogen infection and tissue injury. On the other hand, mononuclear phagocytes, which include circulating macrophages, dendritic cells, and tissue-resident macrophages (osteoclasts in the bone, microglia in the brain, and Kupffer cells in the liver), not only play important roles in inflammatory response but also participate in organogenesis and tissue regeneration. 2,3 Despite differences in morphology and biologic function, polymorphonuclear and mononuclear phagocytes are thought to derive from a common myeloid-restricted population termed neutrophil-macrophage progenitors. 4 These multipotent neutrophil-macrophage progenitors then differentiate to macrophage-dendritic cell progenitors, neutrophil-macrophage progenitors, and basophil-mast cell bipotent progenitors, which in turn undergo terminal differentiation to produce mature dentritic cells, macrophages, neutrophils, basophils, and mast cells. 5 This developmental process is tightly controlled, and dysregulation of phagocyte development and function is associated with several human diseases, including cancer, autoimmune disorders, and neurodegenerative disorders.Interferon regulatory factor-8 (IRF8), also known as the interferon consensus sequence-binding protein, was first identified through screening mouse expression libraries with interferon consensus sequence as a probe. 6 It encodes a transcription factor of IRF family, which contains a highly conserved N-terminal DNA-binding domain and a less conserved C-terminal IRF association domain. 7 Among the 9 members of the mammalian IRF family, IRF4 and IRF8 share the highest similarity in protein sequence and they are predominantly expressed in lymphocytes, macrophages, and dendritic cells. 8 The importance of IRF8 in hematopoiesis is first revealed by genetic studies in IRF8 knockout (IRF8-null) 9 and BXH-2 mutant mice, which carry a loss-of-function mutation in the IRF association domain of IRF8 protein. 10 Both IRF8-null and BXH-2 mutant mice have chronic myeloid leukemia with a profound increase of neutrophil number. 9,10 In addition, loss-of-function mutation in IRF8 gene in these animals also causes a severe reduction of macrophages and dendritic cells. [10][11][12][13] These in vivo studies reveal that IRF8 is essential for myeloid progenitor differentiation toward macrophages but is dispensable for neutrophil development during adult murine myelopoiesis. Subsequent study shows that forced expression of IRF8 in IRF8-deficient myeloid progenitor cell line p...

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Section: Discussionmentioning

confidence: 99%

Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis

Jin

et al. 2011

Blood

146

170

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“…Moreover, several transcription factors, including IRF8, Pu.1, nonphosphorylated STAT1, and C/EBPb, were described to be constitutively bound to the IL-1b promoter and/or enhancer elements, enabling rapid gene transcription upon cellular activation (6,34,(43)(44)(45). Recruitment of NF-kB is one of the crucial steps for initiating IL-1b transcription after stimulation (4)(5)(6)46).…”

Section: Discussionmentioning

confidence: 99%

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

Eigenbrod

Bode

Dalpke

2013

The Journal of Immunology

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The significance of bacterial RNA recognition for initiating innate immune responses against invading pathogens has only recently started to be elucidated. Bacterial RNA is an important trigger of inflammasome activation, resulting in caspase-1–dependent cleavage of pro–IL-1β into the active form. It was reported previously that prolonged treatment with IFN-γ can inhibit IL-1β production at the level of both transcription and Nlrp3 inflammasome activation in an NO-dependent manner. As a result of the delayed kinetics of NO generation after IFN-γ stimulation, these effects were only observed at later time points. We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages and dendritic cells by an additional, very rapid mechanism that was independent of NO. Costimulation with IFN-γ selectively attenuated binding of NF-κB p65 to the IL-1β promoter, thus representing a novel mechanism of IL-1β inhibition by IFN-γ. Transcriptional silencing was specific for IL-1β because expression of other proinflammatory cytokines, such as TNF, IL-6, and IL-12p40, was not affected. Furthermore, by suppressing IL-1β production, IFN-γ impaired differentiation of Th17 cells and production of neutrophil chemotactic factor CXCL1 in vitro. The findings provide evidence for a rapid immune-modulating effect of IFN-γ independent of NO.

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“…The IRF9 nuclear localization signal is contained within the DNA binding domain and is conserved in IRF8 and IRF4 (50), and it is possible that these IRFs could be inducibly retained by STAT1 in the cytoplasm of macrophages, upon S727 phosphorylation. In support of such a mechanism, IRF8 was reported to bind to nontyrosine-phosphorylated STAT1 (51). Other IRF family members are also candidates.…”

Section: Figurementioning

confidence: 94%

Differential Effects of CpG DNA on IFN-β Induction and STAT1 Activation in Murine Macrophages versus Dendritic Cells: Alternatively Activated STAT1 Negatively Regulates TLR Signaling in Macrophages

Schroder

Spille

Pilz

et al. 2007

The Journal of Immunology

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Classical STAT1 activation in response to TLR agonists occurs by phosphorylation of the Y701 and S727 residues through autocrine type I IFN signaling and p38 MAPK signaling, respectively. In this study, we report that the TLR9 agonist CpG DNA induced Ifn-β mRNA, as well as downstream type I IFN-dependent genes, in a MyD88-dependent manner in mouse myeloid dendritic cells. This pathway was required for maximal TNF and IL-6 secretion, as well as expression of cell surface costimulatory molecules. By contrast, neither A- nor B-type CpG-containing oligonucleotides induced Ifn-β in mouse bone marrow-derived macrophages (BMM) and a CpG-B oligonucleotide did not induce IFn-β in the macrophage-like cell line, J774. In BMM, STAT1 was alternatively activated (phosphorylated on S727, but not Y701), and was retained in the cytoplasm in response to CpG DNA. CpG DNA responses were altered in BMM from STAT1S727A mice; Il-12p40 and Cox-2 mRNAs were more highly induced, whereas Tlr4 and Tlr9 mRNAs were more repressed. The data suggest a novel inhibitory function for cytoplasmic STAT1 in response to TLR agonists that activate p38 MAPK but do not elicit type I IFN production. Indeed, the TLR7 agonist, R837, failed to induce Ifn-β mRNA and consequently triggered STAT1 phosphorylation on S727, but not Y701, in human monocyte-derived macrophages. The differential activation of Ifn-β and STAT1 by CpG DNA in mouse macrophages vs dendritic cells provides a likely mechanism for their divergent roles in priming the adaptive immune response.

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Phosphorylation of IRF8 in a pre-associated complex with Spi-1/PU.1 and non-phosphorylated Stat1 is critical for LPS induction of the IL1B gene

Cited by 44 publications

References 61 publications

Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis

Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

Differential Effects of CpG DNA on IFN-β Induction and STAT1 Activation in Murine Macrophages versus Dendritic Cells: Alternatively Activated STAT1 Negatively Regulates TLR Signaling in Macrophages

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