Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ

Do-Umehara, Hanh Chi; Chen, Cong; Urich, Daniela; Zhou, Liang; Qiu, Ju; Jang, Samuel; Zander, Alia; Baker, Margaret; Eilers, Martin; Sporn, Peter H. S.; Ridge, Karen M.; Sznajder, Jacob I.; Budinger, G. R. Scott; Mutlu, Gökhan M.; Lin, Anning; Liu, Jing

doi:10.1038/ni.2566

Cited by 74 publications

(81 citation statements)

References 49 publications

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“…Accordingly, BCL6-deficient macrophages were hypersensitive to LPS. Similarly, deletion of the BTB domain from the Myc-interacting zinc finger protein 1 (MIZ1) (encoded by the Zbtb17 gene), induced a hyperinflammatory response to LPS (23). In this instance, phosphorylation of MIZ1 enabled the protein to recruit HDAC1 to establish a repressive transcriptional complex.…”

Section: Discussionmentioning

confidence: 99%

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

Sadler

Rossello

et al. 2015

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

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Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.

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Section: Discussionmentioning

confidence: 99%

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

Sadler

Rossello

et al. 2015

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

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“…The negative effects of alcohol consumption have been linked to an increased inflammatory response, including increased cytokine release (14,15,37,38). Pro-inflammatory cytokines such as IL-1β, TNF, IL-6 and IL-8 have been identified as important contributors to the pathogenesis of organ damage, including lung as well as liver injury in models of acute inflammation (17)(18)(19)(39)(40)(41)(42). Together with IL-6, IL-8 binds to molecules that are involved in neutrophil activation, trafficking and infiltration of tissues in models of acute lung and liver injury (18,43).…”

Section: Discussionmentioning

confidence: 99%

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

Relja

Omid

Wagner

et al. 2015

International Journal of Molecular Medicine

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Abstract. Increases in pro-inflammatory cytokine levels and tissue-infiltrating leukocytes have been closely linked to increased systemic and local inflammation, which result in organ injury. Previously, we demonstrated the beneficial and hepatoprotective anti-inflammatory effects of acute ethanol (EtOH) ingestion in an in vivo model of acute inflammation. Due to its undesirable side-effects, however, EtOH does not represent a therapeutic option for treatment of acute inflammation. Therefore, in this study, we compared the effects of acute EtOH exposure with ethyl pyruvate (EtP) as an alternative anti-inflammatory drug in an in vitro model of hepatic and pulmonary inflammation. Human hepatocellular carcinoma cells Huh7 and alveolar epithelial cells A549 were stimulated with either interleukin (IL) IL-1β (1 ng/ml, 24 h) or tumor necrosis factor (TNF) (10 ng/ml, 4 h), and then treated with EtP (2.5-10 mM), sodium pyruvate (NaP, 10 mM) or EtOH (85-170 mM) for 1 h. IL-6 or IL-8 release from Huh7 or A549 cells, respectively, was measured by an enzyme-linked immunosorbent assay. Neutrophil adhesion to cell monolayers and CD54 expression were also analyzed. Bcl-2 and Bax gene expression was determined by RT-qPCR, and western blot analysis was performed to determine the mechanisms involved. Treating A549 cells with either EtOH or EtP significantly reduced the IL-1β-or TNF-induced IL-8 release, whereas treating Huh7 cells did not significantly alter IL-6 release. Similarly, neutrophil adhesion to stimulated A549 cells was significantly reduced by EtOH or EtP, whereas for Huh7 cells the tendency for reduced neutrophil adhesion rates by EtOH or EtP was not significant. CD54 expression was noticeably reduced in A549 cells, but this was not the case in Huh7 cells after treatment. The Bax/ Bcl-2 ratio was dose-dependently decreased by EtOH and by high-dose EtP in A549 cells, indicating a reduction in apoptosis, whereas this effect was not observed in Huh7 cells. The underlying mechanisms involve reduced phosphorylation of Akt and nuclear factor-κB (NF-κB) p65. We noted that as with EtP, EtOH reduced the inflammatory response in lung epithelial cells under acute inflammatory conditions. However, due to the low impact which EtP and EtOH had on the hepatocellular cells, our data suggest that both substances exerted different effects depending on the cellular entity. The possible underlying mechanisms involved the downregulation of Akt and the transcription factor NF-κB, but further research on this subject is required.

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“…MiR-127 renders mice more susceptible to endotoxin-induced lung injury and sepsis Next, we assessed the in vivo function of miR-127 using a murine model of lung inflammation and injury induced by LPS (26). The data showed that, compared with the control animals, the mice pretreated with miR-127 exhibited more severe alveolar damage, as evidenced by the increased interstitial edema and debris deposit in the air space (Fig.…”

Section: Mir-127 Promotes M1 Signature Gene Expression While Repressimentioning

confidence: 98%

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

Ying

Kang

Zhang

et al. 2015

The Journal of Immunology

185

122

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A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127–mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti–miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.

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Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ

Cited by 74 publications

References 49 publications

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs

Ethanol, ethyl and sodium pyruvate decrease the inflammatory responses of human lung epithelial cells via Akt and NF-κB in vitro but have a low impact on hepatocellular cells

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

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