scholarly journals Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xuening Wang ◽  
Dan Cheng ◽  
Guanglei Hu ◽  
Lili Liang ◽  
Fei Tan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Receptor Expression ◽  
Structural Basis ◽  
Tnf Receptor ◽  
Death Domain ◽  
Independent Manner ◽  
Normal Keratinocytes ◽  
Apoptosis Protein ◽  
Necrosis Factor

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK’s regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

scholarly journals The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

2001 ◽  
Vol 21 (12) ◽  
pp. 3986-3994 ◽  
Author(s):  
Anne Devin ◽  
Yong Lin ◽  
Shoji Yamaoka ◽  
Zhiwei Li ◽  
Michael Karin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Death Domain ◽  
Iκb Kinase ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

Tumor necrosis factor-α inhibitors alleviation of experimentally induced neuropathic pain is associated with modulation of TNF receptor expression

2014 ◽  
Vol 92 (11) ◽  
pp. 1490-1498 ◽  
Author(s):  
Pablo Andrade ◽  
Govert Hoogland ◽  
John S. Del Rosario ◽  
Harry W. Steinbusch ◽  
Veerle Visser-Vandewalle ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Factor Α ◽  
Necrosis Factor ◽  
Experimentally Induced

Tumor necrosis factor (TNF) interferes with insulin signaling through the p55 TNF receptor death domain

2005 ◽  
Vol 329 (1) ◽  
pp. 397-405 ◽  
Author(s):  
Susan-Beatrice Csehi ◽  
Sabine Mathieu ◽  
Ulrike Seifert ◽  
Arne Lange ◽  
Margit Zweyer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Insulin Signaling ◽  
Tumor Necrosis ◽  
Tnf Receptor ◽  
Death Domain ◽  
Necrosis Factor

The Effect of a Metalloproteinase Inhibitor (GI5402) on Tumor Necrosis Factor- (TNF-) and TNF- Receptors During Human Endotoxemia

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Pascale E.P. Dekkers ◽  
Fanny N. Lauw ◽  
Tessa ten Hove ◽  
Anje A. te Velde ◽  
Philip Lumley ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Surface Expression ◽  
Receptor Expression ◽  
Tnf Receptor ◽  
Tnf Receptors ◽  
Proinflammatory Effect ◽  
Necrosis Factor

Tumor necrosis factor- (TNF-) is released from the cell surface by cleavage of pro–TNF- by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-, but also to enhance the surface expression of TNF- and TNF- receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (−20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF- release (P < .001), but did not influence the increase in monocyte-bound TNF-. In addition, GI5402 attenuated the rise in plasma-soluble TNF- receptors types I and II after LPS injection (both P < .001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF- receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF- is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF- and TNF- receptor number.

scholarly journals Autocrine Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) α Differentially Modulate Cellular Sensitivity to TNF/LT-α Cytotoxicity in L929 Cells

1998 ◽  
Vol 143 (7) ◽  
pp. 2057-2065 ◽  
Author(s):  
Els Decoster ◽  
Sigrid Cornelis ◽  
Bart Vanhaesebroeck ◽  
Walter Fiers
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Signal Sequence ◽  
Receptor Expression ◽  
Classical Pathway ◽  
Tnf Receptor ◽  
Endogenous Expression ◽  
Membrane Bound ◽  
Murine Fibrosarcoma ◽  
Necrosis Factor

Tumor necrosis factor (TNF) and lymphotoxin (LT) α are structurally and functionally related cytokines. We expressed the TNF and LT-α genes in murine fibrosarcoma L929r2 cells, which can be sensitized to TNF/LT-α–dependent necrosis by inhibitors of transcription or translation. Autocrine production of murine TNF in L929r2 cells completely downmodulated the expression of the 55- and 75-kD TNF receptors, resulting in resistance to TNF/LT-α cytotoxicity. Partial downmodulation of the 55-kD receptor was observed in human TNF-producing L929r2 cells. In contrast, an unaltered TNF receptor expression was found on LT-α L929r2 transfectants. Hence, although similar cytotoxic effects are induced by extracellularly administered TNF and LT-α, endogenous expression of these cytokines fundamentally differs in the way they modulate TNF receptor expression. Unlike LT-α, secreted by the classical pathway, TNF is first formed as a membrane-bound protein, which is responsible for receptor downmodulation. To explore whether the different pathways for secretion of TNF and LT-α explain this difference, we examined the effect of membrane-bound LT-α expression. This was obtained by exchange of the classical signal sequence of LT-α for the membrane anchor of chicken hepatic lectin. Membrane retention of LT-α resulted indeed in receptor downmodulation and TNF/LT-α resistance. We conclude that membrane retention of newly synthesized TNF or LT-α is absolutely required for receptor downmodulation and TNF/LT-α resistance.

scholarly journals A potential mechanism of "cross-talk" between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other.

1996 ◽  
Vol 183 (3) ◽  
pp. 1271-1275 ◽  
Author(s):  
E E Varfolomeev ◽  
M P Boldin ◽  
T M Goncharov ◽  
D Wallach
Keyword(s):  
Tumor Necrosis Factor ◽  
Cross Talk ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Functional Expression ◽  
Sequence Motif ◽  
Tnf Receptor ◽  
Death Domain ◽  
Cytoplasmic Proteins ◽  
Necrosis Factor

The p55 tumor necrosis factor (TNF) receptor and Fas/APO1 induce cell death via distinct regions in their intracellular domains. Three cytoplasmic proteins that bind to these receptor regions have been identified recently. One, MORT1 (also called FADD), binds to Fas/APO1 but not to p55-R; another, TRADD, binds to the p55 TNF receptor but not to Fas/APO1; and the third, RIP, binds weakly to both receptors. The regions within these proteins that are involved in binding to the receptors and the receptor regions to which they bind share a common sequence motif, that of the "death domain." This study shows that the death domain motifs in MORT1, TRADD, and RIP bind effectively to each other, a mode of binding that may allow "cross-talk" between the functional expression of the p55 TNF receptor and Fas/APO1.

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