NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation

Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB–dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)–dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB–dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.

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TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Journal of Experimental Medicine ◽

10.1084/jem.185.7.1275 ◽

1997 ◽

Vol 185 (7) ◽

pp. 1275-1286 ◽

Cited By ~ 141

Author(s):

Soo Young Lee ◽

Sang Yull Lee ◽

Yongwon Choi

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Cell Activation ◽

Tumor Necrosis Factor Receptor ◽

Interacting Protein ◽

Signaling Complex ◽

Wide Range ◽

Tnfr Superfamily ◽

Necrosis Factor

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.

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TRUSS, a tumor necrosis factor receptor-1-interacting protein, activates c-Jun NH2-terminal kinase and transcription factor AP-1

FEBS Letters ◽

10.1016/j.febslet.2006.06.098 ◽

2006 ◽

Vol 580 (19) ◽

pp. 4591-4596 ◽

Cited By ~ 6

Author(s):

Surinder M. Soond ◽

Jennifer L. Terry ◽

David W.H. Riches

Keyword(s):

Transcription Factor ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Interacting Protein ◽

Necrosis Factor

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T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors.

Journal of Experimental Medicine ◽

10.1084/jem.183.2.669 ◽

1996 ◽

Vol 183 (2) ◽

pp. 669-674 ◽

Cited By ~ 115

Author(s):

S Y Lee ◽

C G Park ◽

Y Choi

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Cell Receptor ◽

Cytoplasmic Domain ◽

Activated T Cells ◽

Necrosis Factor

CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.

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Tumor necrosis factor induces rapid down-regulation of TXNIP in human T cells

Scientific Reports ◽

10.1038/s41598-019-53234-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Trine B. Levring ◽

Martin Kongsbak-Wismann ◽

Anna K. O. Rode ◽

Fatima A. H. Al-Jaberi ◽

Daniel V. Lopez ◽

...

Keyword(s):

T Cells ◽

Tumor Necrosis Factor ◽

Glucose Uptake ◽

Tumor Necrosis ◽

Gradient Centrifugation ◽

Tumor Necrosis Factor Receptor ◽

Down Regulation ◽

Interacting Protein ◽

Human T Cells ◽

Necrosis Factor

Abstract In addition to antigen-driven signals, T cells need co-stimulatory signals for robust activation. Several receptors, including members of the tumor necrosis factor receptor superfamily (TNFRSF), can deliver co-stimulatory signals to T cells. Thioredoxin interacting protein (TXNIP) is an important inhibitor of glucose uptake and cell proliferation, but it is unknown how TXNIP is regulated in T cells. The aim of this study was to determine expression levels and regulation of TXNIP in human T cells. We found that naïve T cells express high levels of TXNIP and that treatment of blood samples with TNF results in rapid down-regulation of TXNIP in the T cells. TNF-induced TXNIP down-regulation correlated with increased glucose uptake. Furthermore, we found that density gradient centrifugation (DGC) induced down-regulation of TXNIP. We demonstrate that DGC induced TNF production that paralleled the TXNIP down-regulation. Treatment of blood with toll-like receptor (TLR) ligands induced TNF production and TXNIP down-regulation, suggesting that damage-associated molecular patterns (DAMPs), such as endogenous TLR ligands, released during DGC play a role in DGC-induced TXNIP down-regulation. Finally, we demonstrate that TNF-induced TXNIP down-regulation is dependent on caspase activity and is caused by caspase-mediated cleavage of TXNIP.

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