Hepatocyte specific NEMO deletion promotes NK/NKT cell dependent liver damage

Beraza, Naiara; Malato, Yann; Sander, LE; Al-Masaoudi, M; Freimuth, Julia; Riethmacher, Dieter; Roskams, Tania; Liedtke, Carole M.

doi:10.1055/s-0029-1191752

Cited by 2 publications

(3 citation statements)

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“…The role of NK cells in Con A-induced liver damage has been controversial. In one report, the data demonstrated that NK cells play a critical role in the pathogenesis of Con A-induced liver damage, because NK cell depletion with asialo-GM1 Ab notably reduced ALT amounts (14). However, another report claimed that NK cells were not necessary for Con A-mediated liver injury (57).…”

Section: Discussionmentioning

confidence: 99%

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IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis

Huang

Yuan

Zhu

et al. 2017

The Journal of Immunology

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Autoimmune hepatitis is a worldwide health problem and significant cause of mortality. However, the disease etiology is largely unknown, which accounts for ineffective treatment and uncontrolled disease progression. In this study, we demonstrated the functional importance of the IL-17C/IL-17RE axis in Con A-induced hepatitis. Elevated IL-17C expression was detected in liver samples of both human and mouse autoimmune hepatitis. IL-17C, produced by hepatocytes, and its specific receptor IL-17RE on liver-resident T cells were both found to be required in Con A-induced liver damage. Mechanistically, IL-17C augmented the expression of IL-2 by intrahepatic CD4+ T cells to promote NK cell activation and liver damage. To our knowledge, our findings thus for the first time defined the indispensable role of IL-17C/IL-17RE in autoimmune hepatitis; this axis may serve as a novel drug target for the treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

“…In addition to T cells, previous studies have also highlighted the essential role of TRAIL-expressing NK cells in response to Con A (14). TRAIL, through its death receptor, could induce apoptosis in hepatocytes (15).…”

mentioning

confidence: 99%

IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis

Huang

Yuan

Zhu

et al. 2017

The Journal of Immunology

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“…Because activation of NF-kB by expression of constitutively active IKK2EE could protect the TAK1 knock out MEFs, activation of NF-kB is both necessary and sufficient to allow survival of TRAIL treated cells. Consistent with this, deletion of IKKc in mouse hepatocytes caused hypersensitivity to TRAIL, resulting in massive liver damage [38].…”

Section: Discussionmentioning

confidence: 61%

Correction: TAK1 Is Required for Survival of Mouse Fibroblasts Treated with TRAIL, and Does So by NF-κB Dependent Induction of cFLIPL

Lluis¹,

Nachbur²,

Cook³

et al. 2010

PLoS ONE

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a ''death ligand''-a member of the TNF superfamily that binds to receptors bearing death domains. As well as causing apoptosis of certain types of tumor cells, TRAIL can activate both NF-kB and JNK signalling pathways. To determine the role of TGF-b-Activated Kinase-1 (TAK1) in TRAIL signalling, we analyzed the effects of adding TRAIL to mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK12/2 MEFs were significantly more sensitive to killing by TRAIL than wild-type MEFs, and failed to activate NF-kB or JNK. Overexpression of IKK2-EE, a constitutive activator of NF-kB, protected TAK12/2 MEFs against TRAIL killing, suggesting that TAK1 activation of NF-kB is critical for the viability of cells treated with TRAIL. Consistent with this model, TRAIL failed to induce the survival genes cIAP2 and cFlipL in the absence of TAK1, whereas activation of NF-kB by IKK2-EE restored the levels of both proteins. Moreover, ectopic expression of cFlipL, but not cIAP2, in TAK12/2 MEFs strongly inhibited TRAIL-induced cell death. These results indicate that cells that survive TRAIL treatment may do so by activation of a TAK1-NF-kB pathway that drives expression of cFlipL, and suggest that TAK1 may be a good target for overcoming TRAIL resistance.

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Hepatocyte specific NEMO deletion promotes NK/NKT cell dependent liver damage

Cited by 2 publications

References 0 publications

IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis

IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis

Correction: TAK1 Is Required for Survival of Mouse Fibroblasts Treated with TRAIL, and Does So by NF-κB Dependent Induction of cFLIPL

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