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TNF activates TNFRSF1A. 973 / 1020
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"Adenoviruses encode RID proteins that promote the internalization of death receptors for Fas, tumor necrosis factor related apoptosis inducing ligand (TRAIL), and tumor necrosis factor receptor 1 (TNFR1), thereby allowing infected cells to withstand these apoptotic stimuli [XREF_BIBR - XREF_BIBR]."
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"It has been reported that apoptotic death receptors such as CD95 [XREF_BIBR], tumor necrosis factor related apoptosis inducing ligand receptor 1, tumor necrosis factor related apoptosis inducing ligand receptor 2 [XREF_BIBR], and tumor necrosis factor receptor 1 [XREF_BIBR] are enriched in the Golgi complex prior to transport to the plasma membrane, thus suggesting that the Golgi complex may play an important role in apoptotic signalling."
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"Specifically, TNFα alters the molecular stoichiometry and modulates the homeostatic synaptic scaling of post-synaptic AMPARs (AMPA (alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptors)-glutamate receptors), increases hippocampal neuronal cell surface GluA-AMPARs and increases excitatory synaptic activity of TNFRSF1A receptors [92–94]."
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"The combination of TNF and TNFR1 induces the change of TNFR1 trimer, resulting in the recruitment and recruitment of a variety of proteins, including PIPK1, TRADD (TNFR related death domain), CIAPI (apoptosis protein 1 inhibitor), CIAP2, TRAF2 (TNFR related factor 2) and TRAF5 [55]."
sparser
"In summary, this study shows that sustained (but not short-term) hyperammonemia induces TNF-a expression in Purkinje neurons; this may be due to the activation of TNFR1 by TNF-a produced in glia (and later also by TNF-a produced in Purkinje cells), which induces the nuclear translocation of NF-κB and the induction of TNF-a mRNA transcription."
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"Two different problems needed to be solved for this approach : a) although TNFR1 is ubiquitously expressed, TNFR2 expression is much more restricted in terms of cell type, b) TNFR2 is efficiently activated only by mTNF which also activates TNFR1; TNFR1 can be activated by soluble TNF as well."
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"Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS)."
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"TNFR1, found on almost all cell types of the CNS, is primarily stimulated by soluble TNF, leading to pro-inflammatory and apoptotic signaling, whereas TNFR2, found on immune cells, endothelial cells, and a subset of neurons, is activated by transmembrane TNF, evoking anti-inflammatory and pro-survival effects [23,24]."
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"96 As icariin is known to block the secretion of TNF-α,98 we speculated that icariin inhibits the TNF signaling pathway and TNFRSF1A to prevent AD progression.The autophagy-lysosome system plays an important role in the pathogenesis of AD.99 Genetic deficiency of MAPK14 stimulated autophagy, leading to reduced amyloid pathology via enhanced autophagic–lysosomal degradation of BACE1.99 Thus, the suppression of MAPK14 activity is a potential therapeutic strategy to mitigate neurodegeneration in AD."
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"This augmentation occurs either directly through the stimulation of TNFR1 by TNF released from necrotic cells or indirectly through the recruitment and activation of leukocytes including macrophages, neutrophils, lymphocytes, and other proinflammatory cells that contribute to tissue injury (Linkermann et al., 2014; Anders, 2018)."
eidos
"Fig. 1 : Complex I : stimulation of TNFR1 by TNF promotes the formation of an intracellular signalling complex associated with the death domain of trimerized TNFR1 that recruits two death domain-containing proteins : adaptor protein TRADD and receptor-interacting serine / threonine-protein kinase 1 ( RIPK1 ) ."
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"TNFR1, which is activated by both soluble and transmembrane TNF (with a higher affinity for soluble TNF) , is implicated in promoting pro-inflammatory responses , whereas, TNFR2, which is only fully activated by membrane-bound TNF, has been reported to mediate both neuroprotection and remyelination ."
sparser
"The increase of CCL2 in Purkinje neurons and of BDNF in microglia are reversed by blocking S1PR2 with JTE-013 (1-[1,3-Dimethyl-4-(2-methylethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl]-4-(2,6-dichloro-4-pyridinyl)-semicarbazid) indicating that enhanced activation of S1PR2 precedes these effects of hyperammonemia, while activation of TNFR1 by TNFα precedes over-activation of S1PR2, which is reversed by blocking TNFR1 signaling with R7050 (8-Chloro-4-(phenylsulfanyl)-1-(trifluoromethyl)[1,2,4]triazolo [4,3-a]quinoxaline, 8-Chloro-4-(phenylthio)-1-(trifluoromethyl)-[1,2,4]triazolo [4,3-a]quinoxaline) ( xref )."
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"Together, these data indicated that loss of TNFA-R signaling or targeting of TNF-α by neutralizing antibody is protective against CCHFV.Histopathologically, TNFA-R DBL KO mice had a lesser degree of lytic necrosis on both days 4 and 10, compared to WT mice on day 4 (Fig 5A and 5B)."
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"Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant auto-inflammatory disease caused by a heterozygous mutant of tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) on chromosome 12, which is characterized by periodic episodes of fever associated with additional symptoms, including rash, arthralgia, periorbital edema, lymphadenectasis, and hepatosplenomegaly."
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"This occurs through a multicomponent pathway consisting of recruited hepatic macrophages that produce TNF (Figure 3), which, by engaging its type 1 receptor (TNFR1) on hepatocytes, leads to the induction of the critical lipogenic enzymes ACLY, ACC1, and FASN, which convert fructose-derived acetyl-CoA to C16 and C18 fatty acids (Todoric et al., 2020)."
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"However, it remains unclear why TNFα activates TNFR1 rather than TNFR2 in our HIE and OGD models, necessitating further investigation.Research on H3K9 lactylation in regulating inflammatory factors is limited, but studies on H3K9 acetylation in macrophages have garnered attention [45,46,47]."
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"Another category of molecules involved in cell communication that have been demonstrated to be essential to the ACAID mechanism comprises the secreted molecules and their receptors, including CXCR2, DR5, TNF related apoptosis inducing ligands (TRAIL), IFNgamma, IFNgammaR, IL-4, IL-13, IL-6, IL-10, TGFbetaRII, TNFRI, TNFRII, uPA, uPAR, plasminogen, substance P, and neurokinin A."
sparser
"Soluble TNF-activated TNF-R1 recruits the TNFR1-associated death domain (TRADD) protein, which in turn recruits TNF Receptor Associated Factor 2 (TRAF2) and RIPK1 to form the membrane-bound pro-survival complex I. xref TRAF2 is an E3 Ub ligase required for itself and K63-linked ubiquitination of RIPK1."
sparser
"Membrane-bound and soluble TNF strongly interact with two receptors, TNFR1 and TNFR2, but the two forms of TNF are differentially effective in receptor activation. xref Whereas membrane-bound TNF activates TNFR1 and TNFR2 efficiently, soluble TNF is sufficient for TNFR1 activation but largely inactive upon binding to TNFR2."
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"Activation of NF-κB can stimulate the transcription of TNF-α genes, which activate tumor necrosis factor receptor 1 (TNFR1), promoting proinflammatory cytokine production and leading to neuroinflammation, upregulation of cyclooxygenase-2 (COX-2) expression, and apoptosis (Poligone and Baldwin, 2001; Li et al., 2005)."
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"Despite the slight elevations observed in baseline THP-1 adhesion and TNF-induced NF-κB DNA binding, we found no significant racial differences in (1) TNF-induced monocyte adhesion, (2) TNF-induced activation of the TNFR1 signaling complex, or (3) the modulatory effects of HSS on TNFR1 signaling."
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"The molecular mechanisms used by TNFR2 to activate BMX and PI3K/Akt are, however, poorly investigated and their relevance in macrophages has not been addressed so far.In sum, TNFR1 and TNFR2 are differently activated by soluble and membrane TNF, induce production of their own ligand in some cells, engage receptor-specific but also common pathways and the various TNFR1/2-associated signaling pathways are, last but not least, interconnected by regulatory circuits."
sparser
"TNF-α activation of TNFR1 has a pro-inflammatory effect (induction of NF-κB), and induces cell apoptosis (recruitment of TRADD (tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein), Fas associated via death domain, and then activation of caspases 8 and 3). xref "
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"Although TNF-R2 has been shown to independently mediate signals that promote tissue repair through non-classical (alternative) pathways, it is believed that TNF-R2 enhances the function of TNF-R1 by trapping TNF-α.63 The TNF-α-NF-κB positive feedback loop in cancer can be categorized into three main types."
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"In AD, excessive TNF-alpha activated TNFR1 through high affinity binding [XREF_BIBR] and signaling accordingly suppresses Abeta degradation by reducing the expression of insulin degrading enzyme [XREF_BIBR] and affects Abeta production through upregulation of BACE expression [XREF_BIBR] and gamma-secretase activity [XREF_BIBR]."
eidos
"Generally , stimulation of TNFRSF1A by TNF can result in the activation of MAPK ( mitogen-activated protein kinase ) and NFKB / NF-kappaB ( nuclear factor kappa-light-chain-enhancer of activated B cells ) signaling pathways and the transcription of prosurvival genes and proinflammatory cytokines , or the activation of cell death pathways such as extrinsic apoptosis or necroptosis ."
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"XREF_BIBR Lastly, the infection studies in double TNF tm/tm x TNFR1 or R2 -/- transgenic mice rescued protection in TNF tm/tm x TNFR2 -/- mice and comparable protection in TNF tm/tm x TNFR1 -/- mice as in TNF tm/tm mice suggest that membrane signalling though TNFR2 likely provides host protection."
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"XREF_BIBR reported earlier that TNFR2 is a marker associated with increased suppression by human peripheral blood T reg cells, and recently, it was demonstrated that both an agonistic antibody for TNFR2 and a cross linked TNF multimer, which would also activate TNFR1, efficiently expanded T reg cells from healthy donors in vitro."
sparser
"We have shown that induction of motor incoordination by hyperammonemia is mainly mediated by induction of microglia and astrocytes activation in cerebellum, which is associated to increased TNFα, which activates its receptor TNFR1, leading to increased NF-κB in microglia and expression of glutaminase, which increases glutamate, leading to reversal of the GABA transporter GAT3 function in activated astrocytes and increased GABAergic neurotransmission, finally inducing motor incoordination [ xref , xref , xref ]."
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"In contrast to a local secretion of TNFalpha by activated monocytes and macrophages in the intestinal lamina propria, it is also conceivable that systemic TNFalpha is elevated during alcoholic liver disease and activates TNFRI on intestinal epithelial cells to induce tight junction disruption."
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"In contrast, TNFR2 signals via a non-canonical NF-κB pathway and activation of TNFR2 is important for proliferation, survival, and lineage stability of Treg cells, as well as the development of thymic Treg cells from Treg precursor cells (Chen et al., 2013; Mahmud et al., 2014; Salomon, 2021) and is associated with immunoregulation.At physiological concentrations soluble TNF activates TNFR1 but not TNFR2, whereas the membrane bound form of TNF can activate both receptors (Grell et al., 1995)."
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"Several studies have suggested a link between increased TNF-alpha levels and cognitive alteration, and a recent study showed that local increase of TNF-alpha in the hippocampal dentate gyrus activated astrocyte TNF receptor type 1 (TNFR1), which in turn triggered an astrocyte-neuron signaling cascade that resulted in persistent functional modification of hippocampal excitatory synapses."
sparser
"Recently, it has been found that by stimulating the DNA receptor DAI (a DNA-dependent activator of interferon regulatory factor), or activating the death receptor (TNF-α activating TNFR1), FasL, TRAIL, Toll-like receptors (including TRL3 and TRL4, etc.), T-cell antigen receptor, interferon receptor, or virus infection can cause necroptosis [ xref – xref ]."
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"12
,
15
These data strongly suggest a key role of intrathecal inflammation in the slow build‐up of diffuse GM pathology, in particular, in neuronal loss and aberrant rounding morphology, that as previously shown may be mediated by TNF/TNFR1‐mediated necroptosis (rather than apoptosis), possibly related to chronic meningeal inflammation."
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"Tumor necrosis factor receptor associated periodic syndromeTRAPS (OMIM 142680) is an autosomal dominantly inherited disease caused by missense mutations in the tumor necrosis factor (TNF) super family receptor 1A or p55-TNF receptor gene (named TNFRSF1A), located on the short arm of chromosome 12, encoding the 55-kD receptor of TNF [30]."
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"When TNF-R1 and/or -R2 are stimulated by TNF-alpha, the extracellular portions of transmembrane proteins are cleaved, soluble ectodomains are released from the cell surface by a sheddase known as TNF converting enzyme (TACE) XREF_BIBR, and sTNF is neutralized by the sTNF-Rs XREF_BIBR."
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"Generally, stimulation of TNFRSF1A by TNF can result in the activation of MAPK (mitogen activated protein kinase) and NFKB and NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways and the transcription of prosurvival genes and proinflammatory cytokines, or the activation of cell death pathways such as extrinsic apoptosis or necroptosis."
eidos
"Once triggered by TNF-alpha , Fas , TNF-alpha-related apoptosis-inducing ligands and TLR agonists , TNFR1 is activated to form a primary membrane complex known as complex I , which in turn leads to sequential formation of cytoplasmic complex II and the RIP1 / RIP3 / MLKL necrosome and activation of PGAM5 and Drp1 to cause mitochondrial fragmentation and release of intracellular contents such as HMGB1 outside of necrotic cells.9 ,40,41 Necroptosis occurs when caspase-8 activation fails or is inhibited after complex II formation.42 Several studies have reported that necroptosis is involved in the dysfunction of intestinal epithelial cells.43 ,44 Therefore , inhibition of necroptosis could ameliorate cell damage ."
eidos
"The induction of apoptosis or necroptosis or triggering prosurvival NF-kappaB pathway upon stimulation of TNFR1 by TNF-alpha depends on the ubiquitination of RIP1 kinase and on the activity of caspase 8. RIP1 seems to be an important member in regulation of all abovementioned pathways since it is present in each of the three key complexes that mediate downstream signaling of TNFR1 ."
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"Both C33Y TNFR1- and WT TNFR1 transfected SK-Hep-1 cells were treated with TNF-alpha under three different conditions : time course of response to constant exposure to 10 ng/mL TNF-alpha; pulse-chase response to 2 min exposure to 10 ng/mL TNF-alpha; dose response of exposure to various concentrations of TNF-alpha for 30 min."
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"Excessive activation of TNFR1 by TNF leads to the apoptosis of hepatocytes, and thus leads to organ damage; however, membrane bound TNFR1 can be cleaved through proteolytic shedding of its ectodomain, which is dependent on activation of TNF converting enzyme (TACE, also known as ADAM17)."
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"These data show that the pathological changes of the glomerular endothelium and glomerular ESL are likely mediated by TNF-alpha released during endotoxemia and acting through TNFR1, since the LPS induced pathological changes were abolished in Tnfr1 -/- mice and administration of TNF alone induced similar pathological changes."
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"The percentage of expression and MFI of TNFR1 was dramatically increased when ECFCs were treated with low doses of TNFalpha (0.01 and 0.1 ng/ml) and then reached to basal level in intermediate doses of 1 and 10ng/ml and elevated again following high doses of 50 and 100ng/ml of TNFalpha treatment."
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"These findings reveal the necessity of PLAD mediated, ligand independent TNFR1 dimerization for NF-kB activation, highlight the PLAD as central regulator of TNFalpha induced TNFR1 oligomerization, and demonstrate that TNFR1-mEos2 MEFs can be used to investigate TNFR1 antagonizing compounds employing single-molecule quantification and functional NF-kB assays at physiologic conditions."
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"Necroptosis can be induced through ligation of tumor necrosis factor (TNF) members (through TNFR1, TNFR2, TRAILR1, and TRAILR2), Fas ligand, toll like receptors, lipopolysaccharides (LPS), and genotoxic stress [XREF_BIBR - XREF_BIBR] As described earlier, ligation of TNFalpha activates TNFR1 and in turn induces the recruitment of RIP1 kinase via adaptor protein TRADD [XREF_BIBR, XREF_BIBR], to the membrane."
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"Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFalpha dependent manner, A172 glioblastoma cells undergo BV6 induced apoptosis largely independently of TNFalpha and TNFR1, as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown provide little protection."
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"In the extrinsic pathway, apoptosis begins after activation of the death domain receptors by the tumor necrosis factor (TNF) family of proteins including Fas activated by the FasL ligand, TNF-related apoptosis-inducing ligand (TRAIL) receptors 1 and 2 activated by TRAIL, and TNF receptor 1 (TNF-R1) activated by TNF [21,22]."
sparser
"TNF-α binds and activates Tumor necrosis factor receptor 1 (TNFR1), leading to the assembly of complex I, which is composed of TNF receptor-associated factor 2 (Traf2), TNFR1-associated death domain protein (TRADD), RIPK1, cellular inhibitor of apoptosis protein-1 (cIAP1), the tumor-suppressor cylindromatosis (CYLD) and the linear ubiquitin chain assembly complex (LUBAC)."
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"However, our study highlights the fact that TNFalpha and TNFR1 is not the only death receptor ligand and receptor system that can mediate Smac mimetic induced apoptosis, as the TNFalpha blocking antibody Enbrel or TNFR1 knockdown largely fail to rescue BV6 induced apoptosis in A172 glioblastoma cells."
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"Activation of TNFR1 by TNFalpha leads to the rapid recruitment of RIPK1, TNF receptor associated death domain (TRADD), TNF receptor associated factor 2 (TRAF2) and E3 ubiquitin ligases, cellular inhibitor of apoptosis protein 1/2 (cIAP1/2), to form complex I, also called TNFR1-signaling-complex (TNF-RSC), associated with the intracellular domain of TNFR1."
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"They function similarly to endogenous SMAC by antagonizing the inhibition of caspases mediated by XIAP and by inducing the auto-ubiquitination of cIAP1 or cIAP2; subsequent NF-kappaB-induced expression of TNFalpha further activates pro apoptotic TNFR1 (TNFalpha receptor) signaling [XREF_BIBR - XREF_BIBR]."
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"Also, elevated TNF-α levels in EVs from hyperammonemic rats' blood activate the TNF receptor 1 (TNFR1)/C–C motif chemokine ligand 2 (CCL2)/BDNF/tropomyosin receptor kinase B (TrkB)/KCC2 and TNFR1/NF-kB/glutaminase/GABA transporter 3 (GAT3) pathways, thereby enhancing cerebellar GABAergic neurotransmission."
sparser
"The mechanisms by which enhanced activation of TNFR1 by TNFα enhances GABAergic neurotransmission and induce motor incoordination have been already described in detail in our previous studies at 4–5 weeks of hyperammonemia [ xref , xref ] and involve enhanced activation of the TNFα-TNFR1-S1PR2-CCL2-CCR2-BDNF-TrkB pathway which increase membrane expression of GABA A receptor subunits and of KCC2, leading to enhanced GABAergic neurotransmission [ xref , xref ], which is responsible for motor incoordination in hyperammonemic rats [ xref , xref , xref , xref , xref , xref ]."
sparser
"These data not only indicate an important role for TNFR2 in DC survival, but also demonstrate that TNFR1- and TNFR2-mediated rescue is independent of each other and that sTNF is not capable of efficiently activating TNFR2 in moDC, whereas membrane-bound TNF potently activates both TNFR1 and TNFR2 in these cells."
sparser
"Activation of TNFR1 (TNF receptor 1) by TNFα sets off a rapid chain of intracellular signaling events, including dynamic post-translational modifications such as multiple types of ubiquitination, deubiquitination, and phosphorylation, leading to the formation of distinct protein complexes, which in turn dictate cellular responses."
sparser
"Excessive activation of TNFR1 by TNF leads to the apoptosis of hepatocytes, and thus leads to organ damage ( xref ); however, membrane-bound TNFR1 can be cleaved through proteolytic shedding of its ectodomain, which is dependent on activation of TNF-converting enzyme (TACE, also known as ADAM17) ( xref )."
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"It is known that TNF triggers the formation of a TNF receptor 1 (TNFR1) signaling complex by recruiting several effectors such as TNFR1 associated death domain protein (TRADD), receptor interacting protein kinase 1 (RIP1) and TNFR associated factor 2 (TRAF2) to mediate the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) and mitogen activaed protein (MAP) kinases XREF_BIBR, XREF_BIBR."
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"These seemingly opposing functions of TNFR2 stimulation may also explain the contradictory effect of KC in the defense against tumors as mentioned above.By contrast, TNFa stimulation of TNFR1 mostly reduces apoptosis through induction of NFkB leading to the production of many antiapoptotic proteins (50) and suppression of caspases."
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"The unexpected name giving apoptosis-inducing activity of the TWEAK/Fn14 system has been traced back to a cooperative indirect mechanism comprising (i) sensitization for death receptor-induced killing by depletion of protective TRAF2-cIAP1 and TRAF2-cIAP2 complexes, and (ii) cell-type-specific induction of TNF and subsequent stimulation of the prototypic death receptor TNFR1 ."
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"When the nuclear factor-B (NF-B) pathway is blocked, TNF triggers neuronal death by activating TNF receptor 1 (TNFR1) and recruiting caspase 8, while IL-1 causes synaptic loss by causing presynaptic glutamate release and postsynaptic N-methyl-d-aspartate (NMDA) receptor activation via increasing prostaglandin E2 synthesis [76]."
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"The increase of CCL2 in Purkinje neurons and of BDNF in microglia are reversed by blocking S1PR2 with JTE-013 (1-[1,3-Dimethyl-4-(2-methylethyl)-1H-pyrazolo [3,4-b]pyridin-6-yl]-4-(2,6-dichloro-4-pyridinyl)-semicarbazid) indicating that enhanced activation of S1PR2 precedes these effects of hyperammonemia, while activation of TNFR1 by TNFα precedes over-activation of S1PR2, which is reversed by blocking TNFR1 signaling with R7050 (8-Chloro-4-(phenylsulfanyl)-1-(trifluoromethyl)[1,2,4]triazolo [4,3-a]quinoxaline, 8-Chloro-4-(phenylthio)-1-(trifluoromethyl)-[1,2,4]triazolo [4,3-a]quinoxaline) (Arenas et al., 2022a)."
sparser
"Activation of TNFR1 by TNFα leads to the rapid recruitment of RIPK1, TNF receptor-associated death domain (TRADD), TNF receptor-associated factor 2 (TRAF2) and E3 ubiquitin ligases, cellular inhibitor of apoptosis protein 1/2 (cIAP1/2), to form complex I, also called TNFR1-signaling-complex (TNF-RSC), associated with the intracellular domain of TNFR1."
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"Studies have shown that the activation of TNFR1 by TNFα promotes the formation of a complex containing TNFR-related death domain, Ser/Thr kinase receptor interacting protein 1, and TRAF-2, which triggers the activation of NF-κB. Signaling pathways, such as those of MAP kinase (MAPK) and p38 induce inflammation (10-12)."
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"We found that TRADD is essential for induction of the four most studied consequences of TNF induced TNFR1 signaling in mouse embryonic fibroblasts (MEFs), namely the activation of NF-kappaB, the activation of MAP kinases, the induction of necrotic cell death, and the initiation of apoptosis."
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"XREF_BIBR, XREF_BIBR In contrast to the critical role of IFNbeta for BV6 and TMZ induced apoptosis that we discovered in the current study, we previously reported that TNFalpha, another prototypic NF-kappaB target gene, is largely dispensable for BV6 and TMZ induced apoptosis, as addition of the TNFalpha blocking antibody Enbrel or TNFR1 knockdown failed to rescue apoptosis upon combination treatment."
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"Through the binding of death-inducing ligands like tumor necrosis factor-related apoptosis-inducing ligand (TRAIL-R1/2), Fas (FasL) and tumor necrosis factor receptor 1 to their corresponding receptors like TNF (TNFR), Fas (FasR) and death receptors (DR4 and DR5), ROS has been shown to initiate the extrinsic pathway of apoptosis."
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"These terms will dictate theupcoming narrative around the necroptotic molecular players and recent scientific research findings, depicted in Fig. 2.InitiationLigand-receptor interactions are external stimuli for initiation of necroptosis, namely by TNFa induced TNFR1, interferon (IFN) induced IFN receptor (IFNR),66 and FASL induced FAS 67 signaling."
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"Since interaction of C12 with the plasma membrane results in TNF independent activation of TNFR1 mediated apoptotic signaling, we examined the subcellular localization of TNFR1, TRADD (TNF receptor associated death domain), DR5, the apoptotic adaptor protein FADD, caspase-8, and the vault components in CBM simulated by C12 or TNF."
sparser
"The destination depends on the modification states switching between ubiquitination and phosphorylation. xref On the condition that TNFR1 is activated by TNF-α, ubiquitination of RIPK1 by cIAPs and LUBAC results in cell alive through NF-κB signal pathway, xref and deubiquitination of RIPK1 leads to apoptosis xref or necroptosis which is determined by its phosphorylation states. xref Once phosphorylated, RIPK1 then catalyzes the phosphorylation of RIPK3, which launches necroptosis and can be inhibited by necrostatin-1 (Nec-1), the specific inhibitor of RIPK1."
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"The physiological relevance of membrane TNF containing exosomes, however, is currently fully unclear, but a possible function could be TNFR2 stimulation on cells that have no direct contact with TNF producing cells.The complex connection of TNFR1 and TNFR2 signaling along with the dichotomous nature of TNFR1- and TNFR2associated signaling pathways (TNFR1 : strong inflammation, cell death; TNFR2 : mildly inflammatory, cell protection) result in vivo in unique receptor specific functions but also in additive, synergistic or even opposing activities."
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"Recently, the same group has demonstrated that IRF8-dependent DC-biased precursors express membrane-bound TNF, which activates TNF receptor (TNFR) 2 rather than TNFR1, promoting the differentiation of thymus seeding hematopoietic progenitors into T lineage specified precursors (Liang et al., 2023)."
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"This may explain why we see reduced efficacy with TNF small molecules when TNFR1 signalling is driven by very high TNF concentrations, although it should be noted that these concentrations typically exceed those measured in patients with autoimmune disease such as rheumatoid arthritis 27."
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"TNFR1 can be activated by both soluble and membranous forms of TNF-α, but TNFR2 requires activation by membrane-bound TNF-α.8 A prior study by Hamid et al9 showed that although both the receptors mediate oxidative stress and diastolic dysfunction post-MI, global TNFR1 mice exhibit improved LV remodeling and contractile function, and global TNFR2 mice show exaggerated tissue remodeling during chronic HF.9 Similarly, Duerrschmid et al10 showed that in response to angiotensin II, TNFR1 mice develop less cardiac hypertrophy, remodeling, and hypertension compared with wild-type (WT) and TNFR2 mice."
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"The mechanisms by which enhanced activation of TNFR1 by TNFα enhances GABAergic neurotransmission and induce motor incoordination have been already described in detail in our previous studies at 4–5 weeks of hyperammonemia [9, 10] and involve enhanced activation of the TNFα-TNFR1-S1PR2-CCL2-CCR2-BDNF-TrkB pathway which increase membrane expression of GABA receptor subunits and of KCC2, leading to enhanced GABAergic neurotransmission [9, 10], which is responsible for motor incoordination in hyperammonemic rats [9, 11, 37, 38, 43, 57]."
sparser
"In contrast to wild-type soluble TNF (sTNF), which activates TNFR1 and induces cell death in L929 cells, none of the TNFR2-selective fusion proteins induced cell death in L929 cells ( xref ), verifying that fusion of IL2 to EHD2-sc-mTNF R2 did not impact TNFR2 selectivity of this novel molecule."
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"We infected primary human monocytes and monocyte derived macrophages with the virulent Mycobacterium tuberculosis strain H37Rv and followed the rate of cell death in the absence or presence of a wide concentration range of four different TNF targeted biologicals : infliximab and adalimumab (both monoclonal antibodies to human TNF) and etanercept and polyethylene-glycols TNFR1 (fusion constructs of human TNFR2 and TNFR1, respectively)."
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"The finding that the TNFalpha activation of TNF-R1 signaling of apoptosis or survival is determined, at least in part, by integrin signaling is consistent with the report by other investigators that the matricellular protein known as CCN1 and CYR61 can cooperate with integrins alphavbeta5 and alpha6beta1 and the heparin sulfate proteoglycan-syndecan-4 on fibroblasts to promote TNFalpha pro apoptotic signaling."
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"Consistent with a previous study, 29 autocrine TNFalpha signaling is not involved in BV6 and Drozitumab mediated apoptosis, as pharmacological or genetic inhibition of TNFalpha and TNFR1 signaling by the TNFalpha blocking antibody Enbrel or by RNA interference mediated silencing of TNFR1 failed to prevent BV6 and Drozitumab induced apoptosis."
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"This second wave may determine cell fate according to the extent of DNA damage.61Soluble TNF-activated TNF-R1 recruits the TNFR1-associated death domain (TRADD) protein, which in turn recruits TNF Receptor Associated Factor 2 (TRAF2) and RIPK1 to form the membrane-bound pro-survival complex I.62 TRAF2 is an E3 Ub ligase required for itself and K63-linked ubiquitination of RIPK1."
eidos
"Upon inhibition or inactivation of caspase-8 and cellular Inhibitor of apoptosis protein 1/2 ( cIAP1 / 2 ) , activation of TNF receptor-1 ( TNFR1 ) by TNFalpha induces the formation of TNFR1 signaling complexes , leading to phosphorylation-dependent RIPK1 activation ( Weinlich et al , 2017 ) ."
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"In contrast to wild-type soluble TNF (sTNF), which activates TNFR1 and induces cell death in L929 cells, none of the TNFR2-selective fusion proteins induced cell death in L929 cells (
Figure 2C
), verifying that fusion of IL2 to EHD2-sc-mTNF did not impact TNFR2 selectivity of this novel molecule."
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"In our data, TNF-α activates TNFR1 to stimulate downstream signaling components in HCFs.RTKs play an important role in the control of most fundamental cellular processes, including the cell cycle, cell migration, cell metabolism, and survival, as well as cell proliferation and differentiation."
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"To determine whether there were any functional differences in the ability of TNF and LTalpha3 to induce TNFR1 dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTalpha3."
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"Activation of the TNFR1 receptor on neurons initiates the caspase cascade involved in apoptosis [XREF_BIBR] Badiola et al. (2009) using TNFR KO mice and an OGD model in cortical cultures showed that TNF induced apopotic cell death involves TNFR1 activation of caspase-8 and caspase-3 but not caspase-9 [XREF_BIBR]."
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"Under conditions that are insufficient to trigger apoptosis, TNFalpha activates TNFR1 and in turn induces the recruitment of receptor interacting protein 1 (RIP1) kinase and other proteins to form complex I. Subsequently, these proteins dissociate from TNFR1 and RIP1 can be found in the cytosol in complex IIb, which includes RIP1, receptor interacting protein 3 (RIP3) kinase, caspase-8 and FADD."
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"The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-kappaB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy."
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"Importantly, it has been shown that local increase of TNFalpha in the hippocampal dentate gyrus activates astrocytic TNFR1, which in turn triggers an astrocyte-neuron signaling cascade that results in the persistent functional decline of hippocampal excitatory synapses [XREF_BIBR]."
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"TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to the nuclear translocation of NF-κB and the induction of TNF-a expression.The induction of TNF-a by sustained hyperammonemia may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy by altering the function of Purkinje neurons and neurotransmission and by inducing neuronal death.The trafficking and surface membrane expression of AMPA and NMDA receptors is altered by high levels of TNF-a [49–54]."
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"In summary, this study shows that sustained (but not short-term) hyperammonemia induces TNF-a expression in Purkinje neurons; this may be due to the activation of TNFR1 by TNF-a produced in glia (and later also by TNF-a produced in Purkinje cells), which induces the nuclear translocation of NF-κB and the induction of TNF-a mRNA transcription."
sparser
"Notably, TNFR1 is activated by both soluble and transmembrane TNF, whereas TNFR2 is primarily activated by transmembrane TNF. xref TNFR1 is expressed constitutively on most cell types and functions primarily in inflammatory and innate immune responses, while TNFR2 is inducible, mainly expressed by immune, neuronal, and endothelial cells, and functions to mediate homeostatic and regulatory effects. xref A brief comparison between TNFR1 and TNFR2 is outlined in xref ."
eidos
"Activation of TNFR1 by TNFalpha induces the formation of a membrane-associated , intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs ."
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"However, TNF-R1 is expressed in all studied cell lines and it was shown previously that TNF-R2 can induce apoptosis by strongly enhancing the activation of TNF-R1 by TNF-alpha and also by inhibiting nuclear factor kappa B mediated protection, indicating that TNF-R2 overexpression may sensitizes cells to TNF-a-mediated apoptotic signal after gamma irradiation."
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"The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other ironbinding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy related suppression of death by TNF and CHX.IntroductionTNF-mediated activation of TNF receptors TNFRSF1A / TNFR1 and TNFRSF1B and TNFR2 is a powerful inducer of apoptosis and necrosis in vivo and in vitro."
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"Additionally, by activating TNFR1 in airway smooth muscle, TNF-alpha triggers extracellular signal regulated kinase (ERK) and p38 mitogen activated protein kinases (MAPKs) signaling pathway and transcription factors to turn on a variety of genes (interleukins) that mediate inflammatory and immune responses [XREF_BIBR]."
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"In the Results, APG-1387 induces apoptotic cell death through engagement of TNFR1 by TNF-alpha signaling pathway section there was an error : ' We have investigated the expression of NF-kappaB1 and p50 and NF-kappaB2 and p52 by western blot after cells were incubated with various concentrations of APG-1387 '."
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"In these cells, this weak and late signal seemed to be strong enough to induce endogenous expression and secretion of TNF, which in an autocrine manner activated TNFR1 and subsequently the apoptotic signaling-cascade leading to Kym-1 cell death (XREF_FIG), as shown previously XREF_BIBR, XREF_BIBR."
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"Upon TNF stimulation of tumor necrosis factor receptor 1 (TNFR1), RIPK1 is recruited to the TNFR1-associated death structural domain (TRADD), which recruits cIAP1 and cIAP2 via the TRAF2 and linear ubiquitin chain assembly complexes (LUBAC), culminating in complex I formation (28, 106)."
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"If the conditions are not sufficient to induce apoptotic cell death, pro inflammatory mediator TNF alphainitially activates TNFR1 and in turn recruits RIP1 to form complex I. Subsequently, these proteins combine with other components, and can be located in the cytosol in with complex IIb, which includes RIP1, RIP3, caspase-8 and FADD, further leading to necroptosis XREF_BIBR."
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"Additional functional testing is required to explain how variants in genes associated with GO terms related to NF-κB may affect the anti-TNF response.The GO term result death-inducing signaling complex assembly is likely related to TNFR1 signaling, which mediates both the TNF-induced canonical NF-κB pathway and the TNFR1-dependent death induction."
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"This shows that the dynamics of NFκB, PI3K and c3*−p17 being active (Fig. 5) clearly reflects the pro-survival response being the dominant outcome of the TNFα stimulated TNFR1 network.In summary, NFκB, PI3K and c3*−p17 transients extracted from the Boolean dynamics contain strong signatures of the TNFα stimulated TNFR1 network favoring pro-survival phenotype over cell-death at the single-cell level."
sparser
"Next, we investigated the effects of TNFR1 blockade in JAK2 +/VF mice. xref JAK2 +/VF mice were crossed with huTNFR1 ecd mice, as described. xref Because human TNFR1 is activated by mouse TNF-α, using this model allowed us to evaluate the previously characterized anti-human TNFR1 antibody H398 for therapeutic activity. xref "
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"Based on our previous work, indicating that TNF-induced permeabilization in brain metastases was primarily TNFR1-mediated, our aim was to develop a TNFR1-selective mutant of human TNF, that induces permeabilization selectively at sites of brain metastases and could be used clinically."
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"Pre-incubation of CAR-GFP HBEC with TNFR1 blocking antibodies, at a concentration that completely blocked TNFalpha induced TNFR1 activation (Supp Fig. 1I), resulted in reduced THP-1 integration into CAR-GFP HBEC monolayers (XREF_FIG) thus confirming a requirement for TNFR1 in this process."
sparser
"Two different problems needed to be solved for this approach: a) although TNFR1 is ubiquitously expressed, TNFR2 expression is much more restricted in terms of cell type, b) TNFR2 is efficiently activated only by mTNF which also activates TNFR1; TNFR1 can be activated by soluble TNF as well."
sparser
"Studies have shown that the activation of TNFR1 by TNFα promotes the formation of a complex containing TNFR-related death domain, Ser/Thr kinase receptor interacting protein 1, and TRAF-2, which triggers the activation of NF-κB. Signaling pathways, such as those of MAP kinase (MAPK) and p38 induce inflammation ( xref - xref )."
sparser
"However, when the NF-κB-dependent response is inhibited, such as upon genetic deletion of NF-κB, expression of a dominant-negative form of IκBα or in the presence of transcriptional (actinomycin D) or translational (cycloheximide) inhibitors, cells succumb to TNFR1 activation by TNF [ xref , xref ]."
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"For example, tumor necrosis factor-alpha (TNFα), a key proinflammatory cytokine, was shown to increase the frequency of excitatory postsynaptic currents (EPSCs) and N-methyl-D-aspartate (NMDA) currents in lamina II neurons by stimulating TNF receptor subtype-1 and 2 (TNFR1 and TNFR2) in an inflammatory pain model [15]."
sparser
"Despite the slight elevations observed in baseline THP-1 adhesion and TNF-induced NF-κB DNA binding, we found no significant racial differences in (1) TNF-induced monocyte adhesion, (2) TNF-induced activation of the TNFR1 signaling complex, or (3) the modulatory effects of HSS on TNFR1 signaling."