Affinage

TNF

Tumor necrosis factor · UniProt P01375

Round 2 corrected
Length
233 aa
Mass
25.6 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNF is a pleiotropic pro-inflammatory cytokine that governs cell survival, apoptosis, necroptosis, and immune activation by engaging two cognate receptors (TNFR1 and TNFR2) as a homotrimer. It is synthesized as a 26 kDa transmembrane precursor cleaved by ADAM17/TACE (regulated by iRhom2) to release the 17 kDa soluble trimer (PMID:6392892, PMID:9034191, PMID:29369823). Ligand binding to TNFR1 nucleates membrane-proximal complex I (TNFR1–TRADD–RIP1–TRAF2), in which K63-linked polyubiquitination of RIP1 at Lys-377 recruits NEMO and TAK1 to activate NF-κB; when NF-κB-dependent FLIP expression is insufficient, TRADD and RIP1 dissociate into cytoplasmic complex II (FADD–caspase-8) to trigger apoptosis, or, when caspases are inhibited, RIP1 and RIP3 assemble an amyloid-like necrosome that phosphorylates MLKL, driving its trimerization, plasma-membrane translocation, and necroptotic Ca²⁺ influx via TRPM7 (PMID:12887920, PMID:16603398, PMID:22817896, PMID:22265413, PMID:24316671). Beyond cell death, glial-derived TNF mediates homeostatic synaptic scaling of AMPA receptors, TNFR2 signaling promotes oligodendrocyte progenitor proliferation and remyelination, and vagal acetylcholine suppresses macrophage TNF production through a cholinergic anti-inflammatory reflex (PMID:16547515, PMID:11600888, PMID:10839541).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1984 High

    Cloning of human TNF established it as a secreted protein capable of inducing hemorrhagic necrosis of tumors, resolving the molecular identity of 'tumor necrosis factor' activity known from serum studies.

    Evidence cDNA cloning, recombinant expression in E. coli, syngeneic tumor necrosis assay in mice

    PMID:6392892

    Open questions at the time
    • quaternary structure unknown
    • receptor identity unknown
    • processing mechanism uncharacterized
  2. 1985 High

    Demonstration that TNF-α and TNF-β (lymphotoxin) share a common high-affinity receptor (~0.2 nM Kd) unified the two cytokines into one signaling system and showed IFN-γ synergy arises from receptor upregulation.

    Evidence 125I-TNF-α radioligand binding on ME-180 cells with competitive displacement

    PMID:3001529

    Open questions at the time
    • receptor molecular identity not yet cloned
    • intracellular signaling mechanism unknown
  3. 1990 High

    Molecular cloning of TNFR1 (415 aa, cysteine-rich extracellular domain) provided the first structural framework for understanding TNF signal transduction and revealed that soluble TNF-binding protein is its shed ectodomain.

    Evidence Protein purification, peptide sequencing, cDNA cloning, transfection-based 125I-TNF binding

    PMID:2158863

    Open questions at the time
    • intracellular adaptor proteins not identified
    • TNFR2 not yet cloned in this study
  4. 1995 High

    Identification of TRADD as a death-domain adaptor for TNFR1, and demonstration that TRADD bifurcates signaling to TRAF2 (NF-κB) and FADD (apoptosis), established the branching logic of TNF signal transduction.

    Evidence Yeast two-hybrid, co-immunoprecipitation, dominant-negative TRAF2/FADD, CrmA inhibition

    PMID:7758105 PMID:8565075

    Open questions at the time
    • ubiquitin-dependent regulatory steps not yet characterized
    • mechanism of NF-κB pathway suppression of death arm not defined
  5. 1997 High

    Purification and cloning of TACE/ADAM17 as the sheddase that converts 26 kDa transmembrane pro-TNF to 17 kDa soluble TNF resolved how TNF release is regulated at the post-translational level.

    Evidence Purified TACE cleaves recombinant pro-TNF; cDNA cloning confirmed disintegrin metalloproteinase identity

    PMID:9034191

    Open questions at the time
    • upstream regulation of TACE (later shown via iRhom2) unknown
    • contribution of other proteases (MMPs) vs. TACE dominance in vivo not fully resolved
  6. 2000 High

    Multiple discoveries in 2000 expanded TNF biology beyond classical inflammatory cell death: RIP1 kinase activity was shown essential for caspase-independent necrosis; vagal acetylcholine was found to suppress macrophage TNF production (cholinergic anti-inflammatory reflex); and TRAF6/Ubc13 was shown to catalyze K63-linked polyubiquitin chains required for IKK activation.

    Evidence RIP1 KO/kinase-dead reconstitution in T cells; vagus nerve stimulation in rats with macrophage TNF ELISA; in vitro ubiquitination with purified TRAF6/Ubc13/Uev1A

    PMID:10839541 PMID:11057907 PMID:11101870

    Open questions at the time
    • necrosis pathway downstream of RIP1 not mapped (RIP3, MLKL not yet known)
    • neurotransmitter receptor on macrophages mediating cholinergic reflex not identified
    • whether K63-Ub chains form on RIP1 specifically not yet shown
  7. 2003 High

    The two-complex model (membrane complex I for NF-κB, cytoplasmic complex II for apoptosis) explained how a single receptor can trigger opposing outcomes depending on NF-κB-dependent FLIP expression.

    Evidence Sequential co-immunoprecipitation of complex I and complex II, NF-κB inhibitor treatment, FLIP Western blot

    PMID:12887920

    Open questions at the time
    • post-translational modifications governing complex I-to-II transition not fully defined
    • role of deubiquitinases in transition not yet known
  8. 2005 High

    TNF-induced ROS were shown to sustain JNK activation by oxidizing JNK phosphatase catalytic cysteines to sulfenic acid, providing a molecular mechanism for the ROS–JNK amplification loop that promotes cell death.

    Evidence Phosphatase cysteine oxidation assay, JNK activity measurement, SOD overexpression and antioxidant rescue in vitro and in hepatic failure model

    PMID:15766528

    Open questions at the time
    • identity of specific phosphatases oxidized in vivo not resolved
    • relative contribution of ROS-JNK loop vs. direct caspase pathway not quantified
  9. 2006 High

    K63-polyubiquitination of RIP1 at Lys-377 was identified as the critical modification enabling NEMO/IKK recruitment and NF-κB activation from complex I, and glial TNF was shown to mediate homeostatic synaptic AMPA receptor scaling, extending TNF function to neural circuit homeostasis.

    Evidence RIP1 K377R mutagenesis with co-IP of TAK1/IKK; TNF KO neuron–glia co-cultures with mEPSC recordings

    PMID:16547515 PMID:16603398

    Open questions at the time
    • deubiquitinase counterbalancing RIP1 K63-Ub partially addressed later by CYLD
    • TNF receptor subtype mediating synaptic scaling not defined
  10. 2008 High

    Smac-mimetic treatment revealed that cIAP1/2 degradation liberates RIP1, and CYLD deubiquitinase activity on RIP1 K63-Ub chains is required for RIP1-dependent complex II assembly and caspase-8 activation, distinguishing this from the classical cycloheximide-dependent apoptosis pathway.

    Evidence Systematic RNAi of RIPK1/CYLD/cIAP1/2/c-FLIP plus co-IP of signaling complexes with Smac-mimetic

    PMID:18485876

    Open questions at the time
    • in vivo validation of Smac-mimetic pathway not provided
    • quantitative contribution of CYLD vs. other DUBs not resolved
  11. 2009 High

    RIP3 was identified as the obligate kinase partner of RIP1 for programmed necrosis, with RIP3 KO mice resistant to TNF-induced tissue damage, establishing RIP3 as the execution kinase for necroptosis.

    Evidence Genome-wide siRNA screen, RIP3 KO mice and kinase-dead reconstitution, pancreatitis model

    PMID:19524512

    Open questions at the time
    • direct RIP3 substrate not yet identified (MLKL discovered later)
    • necrosome supramolecular structure unknown
  12. 2012 High

    The necroptosis execution pathway was completed: MLKL was identified as the direct RIP3 substrate (phosphorylated at Thr357/Ser358), and RIP1–RIP3 RHIM domains were shown to form functional β-amyloid-like filaments essential for necrosome assembly and kinase cross-activation.

    Evidence Affinity probe pull-down/phospho-site mutagenesis for MLKL; solid-state NMR, X-ray diffraction, amyloid dyes, RHIM mutagenesis for fibril structure

    PMID:22265413 PMID:22817896

    Open questions at the time
    • how phospho-MLKL reaches the plasma membrane not defined
    • membrane permeabilization mechanism of MLKL unclear
  13. 2013 High

    Trimerized phospho-MLKL was shown to translocate to the plasma membrane via its N-terminal coiled-coil domain, where it triggers Ca²⁺ influx through TRPM7, completing the molecular pathway from necrosome to membrane disruption.

    Evidence MLKL domain mutants, subcellular fractionation, Ca²⁺ flux assay, TRPM7 siRNA

    PMID:24316671

    Open questions at the time
    • whether MLKL forms pores directly or acts through TRPM7 exclusively debated
    • lipid-binding specificity of MLKL N-terminal domain not fully characterized
  14. 2018 Medium

    Transmembrane TNF was established as a bidirectional signaling molecule: its retained intracellular domain transmits reverse signals activating ERK–GST-π and NF-κB in tumor cells, and iRhom2 was identified as the upstream regulator of ADAM17-dependent TNF shedding in vivo.

    Evidence tmTNF NTF overexpression/knockdown with xenograft model; iRhom2 KO in lupus-prone mice with transcriptomic and pharmacological epistasis

    PMID:29369823 PMID:29559745

    Open questions at the time
    • structural basis of reverse signaling through tmTNF intracellular domain unknown
    • iRhom2 regulation of TACE substrate selectivity not fully defined
    • reverse signaling findings from single laboratory
  15. 2020 High

    Co-stimulation with TNF and IFN-γ was shown to induce PANoptosis (combined pyroptosis, apoptosis, necroptosis) via JAK/STAT1/IRF1 and iNOS-dependent NO production, with dual cytokine neutralization protecting against SARS-CoV-2, sepsis, and HLH in mice.

    Evidence Cytokine co-treatment, pathway inhibitors, caspase-8/FADD KO, iNOS inhibitor, neutralizing antibodies in multiple mouse models

    PMID:33278357

    Open questions at the time
    • PANoptosis concept and its distinction from sequential independent death pathways still debated
    • human clinical translation of dual neutralization not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of MLKL pore formation versus ion-channel activation at the plasma membrane; how transmembrane TNF reverse signaling is transduced through its short intracellular domain; the receptor subtype and downstream pathway mediating glial TNF-dependent synaptic scaling; and whether PANoptosis represents a mechanistically unified pathway or convergent activation of parallel death programs.
  • MLKL membrane pore versus channel activation mechanism unresolved
  • structural basis of tmTNF reverse signaling unknown
  • TNF receptor subtype for synaptic scaling not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5357801 Programmed Cell Death 9 R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 4 R-HSA-112316 Neuronal System 1
Partners
ADAM17MLKLRIPK1RIPK3TNFRSF1ATNFRSF1BTRADDTRAF2
Complex memberships
RIP1–RIP3 necrosomeTNFR1 complex I (TNFR1–TRADD–RIP1–TRAF2)TNFR1 complex II (TRADD–RIP1–FADD–caspase-8)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Human TNF (tumour necrosis factor) was cloned and sequenced, revealing a precursor structure with ~30% amino acid homology to lymphotoxin; recombinant TNF expressed in E. coli induces haemorrhagic necrosis of transplanted sarcomas in syngeneic mice. cDNA cloning, recombinant protein expression in E. coli, in vivo tumour necrosis assay Nature High 6392892
1985 TNF-α and TNF-β share a common high-affinity receptor on human cells (Kd ~0.2 nM, ~2,000 sites/cell); IFN-γ up-regulates total TNF receptor number 2–3-fold without changing affinity, explaining synergistic anti-tumour effects. 125I-TNF-α radioligand binding assay, receptor characterisation on ME-180 cells, competitive displacement with unlabelled TNF-α/β and IFN-γ Nature High 3001529
1990 A TNF receptor (TNF-R, 415 aa, single-pass transmembrane) with a cysteine-rich extracellular domain homologous to the NGF receptor was cloned; transfected cells specifically bind both TNF-α and TNF-β, and the soluble serum TNF-binding protein is a proteolytic ectodomain of the same receptor. Protein purification, peptide sequencing, cDNA cloning, transfection-based binding assay with 125I-TNF-α and biotinylated TNF-α Cell High 2158863
1995 TRADD (34 kDa) was identified as a specific intracellular binding partner of TNFR1; overexpression of TRADD recapitulates TNF-induced apoptosis and NF-κB activation, and its C-terminal 118 aa are sufficient for both activities and for death-domain interaction with TNFR1. Caspase inhibitor CrmA suppresses TRADD-mediated cell death but not NF-κB activation, demonstrating bifurcation of these two pathways. Yeast two-hybrid, co-immunoprecipitation, overexpression in cell lines, CrmA inhibition assay Cell High 7758105
1995 TRADD directly interacts with TRAF2 (activating NF-κB) and FADD (inducing apoptosis), defining two distinct TNFR1 signalling cascades that bifurcate at TRADD. Dominant-negative TRAF2 (lacking RING domain) blocks NF-κB but not apoptosis; dominant-negative FADD (lacking N-terminal 79 aa) blocks apoptosis but not NF-κB. Co-immunoprecipitation, dominant-negative mutant overexpression, NF-κB reporter assay, cell death assay Cell High 8565075
1995 Matrix metalloproteinases (stromelysin, matrilysin, collagenase, gelatinases) can cleave a recombinant pro-TNF substrate to yield mature TNF in vitro; broad-spectrum MMP inhibitors block pro-TNF processing and suppress serum TNF elevation after endotoxin in rats. In vitro cleavage assay with purified MMPs and recombinant pro-TNF substrate; in vivo rat endotoxin model with MMP inhibitors Journal of leukocyte biology High 7759957
1997 TACE (TNF-α-converting enzyme), a membrane-bound disintegrin metalloproteinase (ADAM17), was purified and cloned; recombinant TACE correctly processes the 26 kDa transmembrane pro-TNF-α precursor to the secreted 17 kDa mature form. Protein purification, cDNA cloning, recombinant enzyme expression, processing assay Nature High 9034191
1998 BRE protein was identified as an interactor of the juxtamembrane domain of p55 TNFR1 (but not p75 TNFR, Fas, or p75 neurotrophin receptor); overexpression of BRE inhibits TNF-α-induced NF-κB activation, positioning it as a modulator of TNFR1 signal transduction. Yeast two-hybrid screen, in vitro binding assay with recombinant fusion proteins, co-immunoprecipitation in transfected mammalian cells, NF-κB reporter assay FASEB journal Medium 9737713
2000 RIP1 kinase activity (not just its scaffold function) is required for caspase-independent necrotic death downstream of Fas, TNF, and TRAIL receptors; FADD and RIP are both required for this alternative necrotic death pathway. Genetic KO primary T cells, RIP kinase-dead mutant reconstitution, caspase inhibition (zVAD), cell death morphology Nature immunology High 11101870
2000 Acetylcholine (the principal vagal neurotransmitter) significantly attenuates TNF release from LPS-stimulated human macrophages in vitro; direct electrical stimulation of the efferent vagus nerve in rats inhibits TNF synthesis in the liver and attenuates peak serum TNF during lethal endotoxaemia. In vitro macrophage stimulation assay; in vivo rodent vagus nerve electrical stimulation with ELISA measurement of serum/tissue TNF Nature High 10839541
2000 TNF-α inhibits thrombus formation and delays arterial occlusion in mice via a mechanism dependent on iNOS-generated nitric oxide in the vessel wall rather than direct platelet action; TNF receptor 1- and 2-deficient mice show normal thrombogenesis in the presence of TNF-α, indicating the effect is not platelet-receptor-mediated. Intravital microscopy in vivo mouse model, TNFR1/TNFR2 KO mice, iNOS KO mice, NOS inhibitor (L-NMMA), platelet aggregation and fibrinogen binding assays The Journal of clinical investigation High 14617760
2000 TRAF6, together with the ubiquitin-conjugating enzyme complex Ubc13/Uev1A, catalyses synthesis of K63-linked polyubiquitin chains; this K63-polyubiquitination is required for IKK activation downstream of TRAF6, establishing a non-proteolytic ubiquitin signalling role in the TNF/NF-κB pathway. Biochemical purification, peptide mass fingerprinting (MS), in vitro ubiquitination assay, proteasome inhibitor controls, IKK activation assay Cell High 11057907
2001 TNF-α (via TNFR2, not TNFR1) promotes proliferation of oligodendrocyte progenitors (NG2+ cells) and is required for remyelination after cuprizone-induced demyelination; TNF-α-deficient mice show significantly delayed remyelination with reduced progenitor pool and mature oligodendrocyte numbers. TNF-α, TNFR1, and TNFR2 knockout mice; cuprizone demyelination model; histology, immunohistochemistry for myelin proteins, EM morphometry, BrdU labelling Nature neuroscience High 11600888
2001 TNF-α directly inhibits CD28 gene transcription in T cells by impairing DNA-protein complex formation at the CD28 minimal promoter initiator sequences and by causing nuclear extracts to fail activation of in vitro transcription from CD28 initiator sequences; continuous exposure generates CD4+CD28null cells. Reporter gene assay, EMSA, in vitro transcription assay, flow cytometry of surface CD28 on T cell lines/clones Journal of immunology Medium 11544310
2003 TNFR1-induced apoptosis proceeds via two sequential complexes: membrane-bound complex I (TNFR1–TRADD–RIP1–TRAF2) rapidly activates NF-κB; TRADD and RIP1 then dissociate to form cytoplasmic complex II with FADD and caspase-8. When NF-κB activation is sufficient, FLIP(L) is incorporated into complex II and the cell survives; failure of NF-κB activation results in apoptosis via complex II. Co-immunoprecipitation of sequential complexes, NF-κB reporter assay, pharmacological NF-κB inhibition, Western blotting for FLIP(L)/caspase-8 Cell High 12887920
2005 TNF-α-induced ROS inhibit JNK-inactivating phosphatases by oxidising their catalytic cysteine to sulfenic acid, causing sustained JNK activation; sustained JNK activity is required for cytochrome c release, caspase-3 cleavage, and necrotic cell death. Mitochondrial SOD suppresses ROS accumulation, and antioxidant treatment prevents both forms of TNF-α-induced cell death. ROS measurement, phosphatase activity assay, cysteine oxidation detection, JNK activity assay, SOD overexpression, antioxidant treatment in cells and in vivo liver failure model Cell High 15766528
2005 A small-molecule inhibitor of TNF-α promotes trimer disassembly by forming an intermediate complex with the intact trimer at 600-fold accelerated subunit dissociation rate, ultimately yielding a dimer–inhibitor complex; X-ray crystal structure shows a single compound molecule displacing one subunit of the trimer. X-ray crystallography, biochemical dissociation kinetics, cell-based and biochemical activity assays (IC50 22 µM biochemical, 4.6 µM cellular) Science High 16284179
2006 Glial cells are the source of TNF-α required for homeostatic synaptic scaling in response to prolonged activity blockade; using wild-type/TNF-α-deficient neuron–glia mixed cultures, TNF-α (from glia) was shown to be necessary for scaling up AMPA receptor content at synapses, implicating glial TNF-α as a mediator of homeostatic plasticity. Mixed wild-type/TNF-α KO neuron–glia co-culture, activity blockade paradigm, AMPA receptor surface expression assay, electrophysiology (miniature EPSC amplitude) Nature High 16547515
2006 TNF-α-induced NF-κB activation requires site-specific K63-linked polyubiquitination of RIP1 at Lys-377; RIP1(K377R) abolishes polyubiquitination and IKK/NF-κB activation, prevents recruitment of TAK1 and IKK complexes to TNFR1, and polyubiquitinated RIP1 recruits IKK via direct binding of NEMO to K63-polyubiquitin chains. In vivo ubiquitination assay, site-directed mutagenesis (K377R), co-immunoprecipitation from TNF receptor complexes, IKK kinase assay, NEMO ubiquitin-binding mutants Molecular cell High 16603398
2008 TNF-α induces two distinct caspase-8 activation pathways: (1) cycloheximide-mediated (c-FLIP depletion, RIPK1-independent); (2) Smac-mimetic-mediated (cIAP1/2 autodegradation → RIPK1 release from TNFR complex → RIPK1/FADD/caspase-8 complex II, requiring CYLD deubiquitinase activity on RIPK1 K63-ubiquitin chains). Smac-mimetic pathway is not blocked by endogenous c-FLIP. Smac mimetic and cycloheximide co-treatment, RNAi knockdown of RIPK1/CYLD/cIAP1/2/c-FLIP, co-immunoprecipitation of signalling complexes, caspase-8 activity assays Cell High 18485876
2009 RIP3 kinase is required for TNF-α-induced programmed necrosis; RIP3 expression levels correlate with necrosis susceptibility across cell lines, its kinase activity is essential, and upon necrosis induction RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. RIP3 KO fibroblasts are resistant to necrosis and RIP3 KO mice are protected from tissue damage in acute pancreatitis. Genome-wide siRNA screen, RIP3 KO mice, kinase-dead mutant reconstitution, co-immunoprecipitation of necrosis complex, pancreatitis model Cell High 19524512
2009 JNK is required for TNF-α expression in hematopoietic cells but not for TNF-α-stimulated death of hepatocytes; hepatocyte-specific JNK1/2 double KO mice develop normal hepatitis, whereas hematopoietic-compartment JNK1/2 double KO mice show profound defect in hepatitis with markedly reduced TNF-α expression. Conditional (hepatocyte-specific and hematopoietic-specific) Jnk1/Jnk2 double KO mice, concanavalin A hepatitis model, TNF-α ELISA, liver damage readouts Cell High 19167327
2011 Rab37 small GTPase controls TNF-α secretion from macrophages; Rab37 expression is induced by LPS, overexpression of wild-type/constitutively active Rab37 increases TNF-α secretion, siRNA knockdown decreases it. Rab37 interacts with Munc13-1, and TNF-α-containing vesicles co-localise with both Rab37 and Munc13-1; Munc13-1 knockdown similarly decreases TNF-α secretion. RT-PCR, siRNA knockdown, overexpression of Rab37 mutants, LC-MS/MS interactome, immunocytochemistry, ELISA of secreted TNF-α European journal of immunology Medium 21805469
2012 RIP1 and RIP3 RHIM domains mediate assembly of heterodimeric filamentous β-amyloid-like structures (confirmed by ThT/Congo red binding, CD, FTIR, X-ray diffraction, solid-state NMR); the endogenous RIP1/RIP3 necrosome from necrotic cells is ultrastable and has fibrillar amyloid core structure; RHIM mutations abolish filament formation, kinase cross-activation, and programmed necrosis in vivo. Solid-state NMR, X-ray diffraction, amyloid dyes, cryo-EM, RHIM mutagenesis, in vivo necrosis assay Cell High 22817896
2012 MLKL (mixed lineage kinase domain-like protein) is a direct substrate and downstream effector of RIP3 in TNF-induced necroptosis; RIP3 phosphorylates MLKL at Thr357/Ser358, and these phosphorylation events are critical for necrosis; necrosulfonamide blocks necrosis by targeting MLKL downstream of RIP3. Affinity probe pull-down, co-immunoprecipitation with anti-RIP3, RNAi knockdown, phospho-site mutagenesis, small-molecule inhibitor (necrosulfonamide) Cell High 22265413
2013 Trimerized MLKL translocates to the plasma membrane during TNF-induced necroptosis via its N-terminal coiled-coil domain; plasma membrane localisation is required for Ca2+ influx, an early event of necroptosis, and TRPM7 is identified as a downstream MLKL target for Ca2+ influx. MLKL mutant overexpression, subcellular fractionation, Ca2+ flux assay, TRPM7 siRNA knockdown, co-immunoprecipitation Nature cell biology High 24316671
2013 Pellino3 (E3 ubiquitin ligase) targets RIP1 in a TNF-dependent manner to inhibit complex II formation and caspase-8-mediated cleavage of RIP1; Pellino3-deficient cells and mice show enhanced TNF-induced apoptosis without affecting NF-κB activation, defining Pellino3 as a regulator of the cell-death/survival balance downstream of TNF. Pellino3 siRNA/KO mice, co-immunoprecipitation of complex II, caspase-8 activity assay, TNF lethality model in vivo Nature communications Medium 24113711
2013 Transmembrane TNF-α (tmTNF-α) on breast cancer cells can act as a reverse-signalling receptor; a monoclonal antibody targeting the membrane-retained N-terminal fragment of tmTNF-α inhibits NF-κB activation and Bcl-2 expression without activating reverse signalling, and suppresses tumour growth and metastasis in vivo. Monoclonal antibody development, in vitro ADCC assay, NF-κB/Bcl-2 Western blot, xenograft mouse model, metastasis assay Cancer research Medium 23794706
2018 Transmembrane TNF-α (tmTNF-α) mediates doxorubicin resistance in breast cancer via reverse signalling through its intracellular domain, activating the ERK–GST-π axis and NF-κB anti-apoptotic pathway; NTF (N-terminal fragment retaining intracellular domain) overexpression confers DOX resistance, reversed by tmTNF-α suppression in combination with chemotherapy in a xenograft model. tmTNF-α/NTF overexpression and siRNA knockdown, Western blotting (ERK, GST-π, NF-κB), flow cytometry (apoptosis), xenograft mouse model Oncogene Medium 29559745
2018 iRhom2 regulates ADAM17 (TACE)-dependent shedding of TNF-α (and HB-EGF); iRhom2 deficiency in lupus-prone Fcgr2b−/− mice simultaneously blocks TNF-α and HB-EGF/EGFR signalling in kidney, protecting against severe lupus nephritis without altering anti-dsDNA antibody production. iRhom2 KO in Fcgr2b−/− mice, pharmacological TNF-α and EGFR blockade, unbiased transcriptome profiling of kidney/macrophages, kidney damage scoring The Journal of clinical investigation Medium 29369823
2020 Co-stimulation with TNF-α and IFN-γ, but not either cytokine alone, induces PANoptosis (inflammatory cell death combining pyroptosis, apoptosis, and necroptosis) via the JAK/STAT1/IRF1 axis, leading to nitric oxide production and caspase-8/FADD-mediated cell death; neutralising both cytokines protects mice from SARS-CoV-2 mortality, sepsis, and haemophagocytic lymphohistiocytosis. Cytokine co-treatment in cell lines, JAK/STAT1/IRF1 pathway inhibitors, caspase-8/FADD KO, iNOS inhibitor, neutralising antibody treatment in multiple in vivo mouse models Cell High 33278357
2019 Cortistatin (CST) competitively binds to both TNFR1 and TNFR2, suppressing TNF-α pro-inflammatory signalling; CST deficiency accelerates OA-like phenotype and exogenous CST attenuates OA development in vivo, with TNFR1/TNFR2 KO mice confirming TNF receptor involvement in CST's protective role. Co-immunoprecipitation, biotin-based solid-phase binding assay, TNFR1/TNFR2 KO mice, OA surgical and spontaneous models, NF-κB pathway analysis EBioMedicine Medium 30826358
2013 EVER2 protein promotes TNF-α- and TRAIL-induced apoptosis by interacting with the N-terminal domain of TRADD, impairing recruitment of TRAF2 and RIPK1 to TRADD and thereby shifting signalling toward apoptosis; a cancer-associated EVER2 allele (I306) shows impaired TRADD binding and reduced TNF-α-induced cell death. Co-immunoprecipitation, cell death assays with TNF-α/TRAIL treatment, EVER2 overexpression/knockdown, allele-specific binding assay Cell death & disease Medium 23429285

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 3164 10839541
2012 Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2249 22265413
2003 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2132 12887920
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2009 Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 1879 19524512
1984 Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1793 6392892
1999 Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1753 10604883
1995 The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1732 7758105
1996 TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1709 8565075
1985 Tumor necrosis factor (TNF). Science (New York, N.Y.) 1598 2413547
2000 Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature immunology 1532 11101870
2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 1526 11057907
2005 Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 1506 15766528
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1997 Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1416 9034191
2007 Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature genetics 1399 17192785
2020 Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell 1359 33278357
2006 Synaptic scaling mediated by glial TNF-alpha. Nature 1357 16547515
2013 A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA psychiatry 1274 22945416
2021 The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. International journal of molecular sciences 1223 33800290
2008 TNF-alpha induces two distinct caspase-8 activation pathways. Cell 1134 18485876
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2013 Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nature cell biology 1109 24316671
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1990 Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 1077 2158863
2000 Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. The Journal of biological chemistry 1058 11085990
1985 Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature 1055 3001529
1994 Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1038 7935762
2012 The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 989 22817896
2002 Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 941 12297050
2009 Systemic inflammation and disease progression in Alzheimer disease. Neurology 887 19738171
2006 Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Molecular cell 849 16603398
2001 TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nature neuroscience 820 11600888
2000 TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microscopy research and technique 800 10891884
2004 Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology (Baltimore, Md.) 781 15239085
2010 Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford, England) 650 20194223
2013 TNF-α signalling and inflammation: interactions between old acquaintances. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 643 23685857
2009 Role of TNF-alpha in vascular dysfunction. Clinical science (London, England : 1979) 551 19118493
2003 Anti-TNF-alpha therapies: the next generation. Nature reviews. Drug discovery 451 12951580
2005 Small-molecule inhibition of TNF-alpha. Science (New York, N.Y.) 418 16284179
2014 Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Frontiers in immunology 337 24592264
2008 Insulin resistance associated to obesity: the link TNF-alpha. Archives of physiology and biochemistry 332 18629684
1999 The role of TNF alpha in adipocyte metabolism. Seminars in cell & developmental biology 325 10355025
2004 The role of TNF-alpha in insulin resistance. Endocrine 307 15146098
2000 Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 304 10652441
1999 Mechanisms of TNF-alpha-induced insulin resistance. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 303 10320052
2007 Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions. Archives of dermatology 268 17310002
2010 TNF-alpha and obesity. Current directions in autoimmunity 249 20173393
1995 TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. Journal of immunology (Baltimore, Md. : 1950) 239 7730642
2001 Down-regulation of CD28 expression by TNF-alpha. Journal of immunology (Baltimore, Md. : 1950) 216 11544310
1995 Matrix metalloproteinases and processing of pro-TNF-alpha. Journal of leukocyte biology 201 7759957
2018 Unleashing endogenous TNF-alpha as a cancer immunotherapeutic. Journal of translational medicine 198 30170620
2011 Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS & neurological disorders drug targets 191 21288189
2008 Depression, comorbidities and the TNF-alpha system. European psychiatry : the journal of the Association of European Psychiatrists 163 18504118
2009 Blocking TNF-alpha attenuates aneurysm formation in a murine model. Journal of immunology (Baltimore, Md. : 1950) 162 19620291
1998 Sleep. A physiologic role for IL-1 beta and TNF-alpha. Annals of the New York Academy of Sciences 160 9917875
2004 Targets for TNF-alpha-induced lipolysis in human adipocytes. Biochemical and biophysical research communications 158 15110769
2013 Regulation of TNF-α with a focus on rheumatoid arthritis. Immunology and cell biology 157 23628802
1991 TNF alpha mRNA expression in allergic inflammation. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 156 1777835
2008 Regulation of PPARgamma function by TNF-alpha. Biochemical and biophysical research communications 149 18655773
2020 Complexity of TNF-α Signaling in Heart Disease. Journal of clinical medicine 127 33053859
2009 Induction of hepatitis by JNK-mediated expression of TNF-alpha. Cell 126 19167327
2015 Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity. Journal of neurochemistry 117 25492727
2007 TNF-alpha alters visfatin and adiponectin levels in human fat. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 106 17447161
2005 TNF-{alpha}, chronic hepatitis C and diabetes: a novel triad. QJM : monthly journal of the Association of Physicians 101 15625348
2006 Modulating TNF-alpha signaling with natural products. Drug discovery today 98 16846800
2008 The TNF-alpha system: functional aspects in depression, narcolepsy and psychopharmacology. Current neuropharmacology 95 19506720
2013 Targeting transmembrane TNF-α suppresses breast cancer growth. Cancer research 84 23794706
2016 TNF-α gene polymorphisms and expression. SpringerPlus 83 27652081
1992 Genomic structure, induction, and production of TNF-alpha. Immunology series 83 1550865
2009 TNF-alpha and its inhibitors in cancer. Medical oncology (Northwood, London, England) 82 19277912
2018 iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. The Journal of clinical investigation 77 29369823
2003 Antithrombotic activity of TNF-alpha. The Journal of clinical investigation 76 14617760
1996 TNF-alpha-induced regulation and signalling in macrophages. Immunobiology 76 8933152
2024 At the Crossroads of TNF α Signaling and Cancer. Current molecular pharmacology 74 37691196
2010 Anti-TNF-alpha therapies in systemic lupus erythematosus. Journal of biomedicine & biotechnology 74 20625488
1999 TNF-alpha regulates corneal Langerhans cell migration. Journal of immunology (Baltimore, Md. : 1950) 74 10201952
2014 Microglial TNF-α mediates enhancement of dopaminergic degeneration by brain angiotensin. Glia 72 24272709
1991 Ubiquitous expression of TNF-alpha/cachectin immunoreactivity in human endometrium. American journal of reproductive immunology (New York, N.Y. : 1989) 67 1741931
2018 Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene 65 29559745
2011 Implications of TNF-α in the pathogenesis and management of GVHD. International journal of hematology 65 21384095
2002 TNF-alpha is involved in activating DNA fragmentation in skeletal muscle. British journal of cancer 65 11953838
2000 TNF-alpha/TNFRI in primary and immortalized first trimester cytotrophoblasts. Placenta 65 10940203
2017 TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells. Cancer cell international 63 28127258
2015 TNF-α: a treatment target or cause of sarcoidosis? Journal of the European Academy of Dermatology and Venereology : JEADV 62 26419478
2006 Anti-TNF-alpha antibody therapies in autoimmune diseases. Current topics in medicinal chemistry 62 17017952
2019 Cortistatin binds to TNF-α receptors and protects against osteoarthritis. EBioMedicine 60 30826358
2016 RIPK1 protects from TNF-α-mediated liver damage during hepatitis. Cell death & disease 59 27831558
2015 The multimerization and secretion of adiponectin are regulated by TNF-alpha. Endocrine 57 26407855
2011 Role of TNF-alpha during central sensitization in preclinical studies. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 57 21559854
2018 Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α. The Journal of allergy and clinical immunology 56 30578874
2012 IL-33 regulates TNF-α dependent effects in synovial fibroblasts. International journal of molecular medicine 55 22246057
2014 TNF-α, a good or bad factor in hematological diseases? Stem cell investigation 54 27358858
2005 Free radicals trigger TNF alpha-induced cardioprotection. Cardiovascular research 54 15621052
2008 Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. Trends in molecular medicine 53 18693138
1990 Sulfasalazine inhibits the binding of TNF alpha to its receptor. Immunopharmacology 52 1981213
2002 Stimulation of TNF alpha expression by hyperosmotic stress. Pflugers Archiv : European journal of physiology 51 11889578
2010 Molecular pathways of spontaneous and TNF-{alpha}-mediated neutrophil apoptosis under intermittent hypoxia. American journal of respiratory cell and molecular biology 47 20870895
2006 Monad, a WD40 repeat protein, promotes apoptosis induced by TNF-alpha. Biochemical and biophysical research communications 47 16487927
2011 Release of TNF-α from macrophages is mediated by small GTPase Rab37. European journal of immunology 46 21805469
2013 TNF-α signaling in Fanconi anemia. Blood cells, molecules & diseases 45 23890415
2013 Resveratrol enhances TNF-α production in human monocytes upon bacterial stimulation. Biochimica et biophysica acta 45 24035785
2009 Infliximab and the TNF-alpha system. American journal of physiology. Gastrointestinal and liver physiology 45 19136378
2014 TNF-α promotes invasive growth through the MET signaling pathway. Molecular oncology 44 25306394
2001 Targets of glucocorticoid action on TNF-alpha release by macrophages. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 44 11506387
2001 Leptin, insulin and TNF-alpha in weight loss. Journal of endocrinological investigation 44 11817710
1998 BRE: a modulator of TNF-alpha action. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 44 9737713
2015 Effects of TNF-α on Cementoblast Differentiation, Mineralization, and Apoptosis. Journal of dental research 43 26088424
2009 IGFBP-3, hypoxia and TNF-alpha inhibit adiponectin transcription. Biochemical and biophysical research communications 43 19324019
2008 Monomeric IgG is neuroprotective via enhancing microglial recycling endocytosis and TNF-alpha. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 19020014
2019 Targeted TNF-α Overexpression Drives Salivary Gland Inflammation. Journal of dental research 42 30958728
2007 Induction of TNF-alpha by LPS in Schwann cell is regulated by MAPK activation signals. Cellular and molecular neurobiology 42 17902045
2002 Perspectives for TNF-alpha-targeting therapies. Arthritis research 42 12110119
2022 TNF-α/anti-TNF-α drugs and its effect on pregnancy outcomes. Expert reviews in molecular medicine 41 35687009
2012 Sulforaphane has opposing effects on TNF-alpha stimulated and unstimulated synoviocytes. Arthritis research & therapy 41 23072510
2007 The role of soluble TNF receptors for TNF-alpha in uveitis. Investigative ophthalmology & visual science 41 17591895
2013 Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α. Nature communications 40 24113711
2017 MicroRNA-155-3p Mediates TNF-α-Inhibited Cementoblast Differentiation. Journal of dental research 38 28692806
2005 TNF(alpha) modulation of visceral and spinal sensory processing. Current pharmaceutical design 38 15853670
2000 TNF-alpha, leptin, and lymphocyte function in human aging. Life sciences 38 11105988
2020 TNF-α signaling regulates RUNX1 function in endothelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 33135824
2019 Effect of TNF-α-Induced Sclerostin on Osteocytes during Orthodontic Tooth Movement. Journal of immunology research 36 31341915
2008 TNF-alpha stimulates Akt by a distinct aPKC-dependent pathway in premalignant keratinocytes. Experimental dermatology 36 18557926
2016 TNF-α downregulates CIDEC via MEK/ERK pathway in human adipocytes. Obesity (Silver Spring, Md.) 33 27062372
2004 Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta neurobiologiae experimentalis 33 15190675
2018 ATF7 mediates TNF-α-induced telomere shortening. Nucleic acids research 32 29490055
2013 EVER2 protein binds TRADD to promote TNF-α-induced apoptosis. Cell death & disease 32 23429285
2006 Association of TNF-alpha genetic polymorphism with HLA DPB1*0301. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 32 17014432
2003 UV induces VEGF through a TNF-alpha independent pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 12551841
2017 Interaction between BDNF and TNF-α genes in schizophrenia. Psychoneuroendocrinology 31 29306772