JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Thomsen, Martin K.; Bakiri, Latifa; Hasenfuss, Sebastian C.; Hamacher, Rainer; Martínez, Lola; Wagner, Erwin F.

doi:10.1172/jci70405

Cited by 51 publications

(37 citation statements)

References 61 publications

(71 reference statements)

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“…Inflammatory cells, particularly T cells, play a central role in the pathogenesis of human AIH as well as in ConA-induced experimental hepatitis 3 18. T cells activated by ConA produce high levels of cytokines, including IFN-γ, tumour necrosis factor (TNF) α and interleukin (IL) 2 20. IFN-γ-STAT1 signalling is essential for experimental ConA-mediated hepatitis both via activation of T cells and by directly inducing hepatocyte death 21.…”

Section: Resultsmentioning

confidence: 99%

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury

Günther

Kremer

et al. 2016

Gut

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Section: Resultsmentioning

confidence: 99%

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury

Günther

Kremer

et al. 2016

Gut

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“…While indirect evidence through overexpression or deficiency of the negative regulator BATF shows that AP-1 activity promotes generation of i NKT cells 44,45 , lack of the Fos family member Fra2 leads to increased i NKT cell numbers 46 . Interestingly, JunB/AP1 directly controls expression of Ifng , a hallmark cytokine released by mature i NKT cells 47 . Our studies using JunB-deficient mice reveal a significant reduction of thymic as well as peripheral i NKT cell numbers.…”

Section: Discussionmentioning

confidence: 99%

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

et al. 2016

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Invariant natural killer T (iNKT) cells are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage-specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. We identified JunB as a novel regulator of iNKT development and show that target gene expression of both JunB and iNKT master transcription factor PLZF was UTX-dependent. We determined iNKT super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for iNKT lineage commitment. These findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms.

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“…signals transduced via the TPL2-ERK pathway regulate the transcription factor JunB (Fig. 9A), which controls the expression of the IFN-g gene in iNKT cells and influences aGalCer-induced inflammatory liver disease in the mouse (34). Our findings also uncover a novel physiological role for TPL2 in Akt activation and show that this signaling axis promotes the nuclear accumulation of NFAT in aGalCer-challenged iNKT cells (Figs.…”

Section: Discussionmentioning

confidence: 56%

“…NFAT is activated by TPL2 overexpression (31), but whether it is a physiological target of TPL2 remains unknown. JunB is a component of the NFAT: AP-1 transcriptional complex that regulates il4 transactivation in mouse T cells (32,33), is upregulated in aGalCer-stimulated iNKT cells, and required for the transcription of the IFN-g gene (34). On the basis of these premises, we analyzed the impact of inhibition of TPL2 kinase activity on aGalCer-induced transcription factor engagement in DN32.D3 cells.…”

Section: Tpl2 Kinase Activity Is Required For Il-4 and Ifn-g Gene Expmentioning

confidence: 99%

TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury

Vyrla

Nikolaidis

Oakley

et al. 2016

The Journal of Immunology

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Invariant NKT (iNKT) cells represent a subset of innate-like T lymphocytes that function as orchestrators of hepatic inflammation underpinning liver damage. In this study, we demonstrate that TPL2, an MAP3 kinase that has mostly been appreciated for its physiological role in macrophage responses, is a signaling factor in CD3+NK1.1+ iNKT cells and mediator of hepatic inflammation. Genetic ablation of TPL2 in the mouse ameliorates liver injury induced by Con A and impinges on hallmarks of NKT cell activation in the liver without affecting NKT cell development in the thymus. The pivotal role of TPL2 in iNKT cell functions is further endorsed by studies using the iNKT-specific ligand α-galactosylceramide, which causes mild hepatitis in the mouse in a TPL2-dependent manner, including production of the effector cytokines IL-4 and IFN-γ, accumulation of neutrophils and licensing and activation of other immune cell types in the liver. A TPL2 kinase inhibitor mirrors the effects of genetic ablation of TPL2 in vivo and uncovers ERK and Akt as the TPL2-regulated signaling pathways responsible for IL-4 and IFN-γ expression through the activation of the transcription factors JunB and NFAT. Collectively, these findings expand our understanding of the mechanisms of iNKT cell activation and suggest that modulation of TPL2 has the potential to minimize the severity of immune-driven liver diseases.

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JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Cited by 51 publications

References 61 publications

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury

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