Affinage

TNF

Tumor necrosis factor · UniProt P01375

Length
233 aa
Mass
25.6 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNF-alpha is a homotrimeric cytokine that acts as a master regulator of inflammation, cell death, and tissue remodeling by engaging two distinct receptors, TNFR1 (p55) and TNFR2 (p75), each bearing cysteine-rich extracellular repeats that recognize the trimeric ligand (PMID:10891884). It is synthesized as a transmembrane precursor that is proteolytically shed to release the soluble cytokine by the TACE/ADAM17 sheddase — itself dependent on iRhom2 — and, independently, by matrix metalloproteinases that process pro-TNF both in vitro and in vivo (PMID:20194223, PMID:29369823, PMID:7759957). The transmembrane form is bidirectional, transmitting forward signals as a ligand and reverse (outside-to-inside) signals back into the producing cell (PMID:20194223). A defining feature of TNF-alpha signaling is its control over caspase-8-dependent death: it engages two mechanistically distinct routes, one driven by loss of c-FLIP and independent of RIPK1, and a second in which cIAP1/2 autodegradation releases RIPK1 to assemble a CYLD-dependent RIPK1–FADD–caspase-8 death complex (PMID:18485876), with RIPK1 acting as a scaffold that protects cells from TNF-driven apoptosis while its kinase activity drives necrotic death (PMID:27831558). Through TNFR1, TNF-alpha precipitates mitochondrial dysfunction and apoptotic tissue loss (PMID:25492727, PMID:11953838), whereas TNFR2 mediates regenerative outputs such as oligodendrocyte progenitor proliferation and remyelination (PMID:11600888). TNF-alpha couples receptor engagement to NF-κB and MAPK cascades (PMID:8933152, PMID:9737713), driving osteocyte RANKL induction and osteoclastogenesis (PMID:31921183), metabolic disruption including IRS-1-mediated insulin resistance and suppression of adiponectin assembly (PMID:10320052, PMID:26407855), and pro-invasive and inflammatory transcriptional programs (PMID:25306394, PMID:32069267). Receptor-blocking and pathway-modulating agents — including the trimer-disassembling small molecule, anti-TNF antibodies, and competitive ligands such as cortistatin — define multiple points at which this signaling can be intercepted (PMID:16284179, PMID:21853060, PMID:30826358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Established that mature soluble TNF-alpha can be liberated from its precursor by proteolytic processing, identifying matrix metalloproteinases as candidate sheddases controlling circulating TNF levels.

    Evidence In vitro cleavage of recombinant pro-TNF by purified MMPs and MMP-inhibitor blockade of TNF release in a rat endotoxin model

    PMID:7759957

    Open questions at the time
    • Did not establish the dominant physiological sheddase versus ADAM17
    • No structural definition of the cleavage site
  2. 1996 Medium

    Defined how TNFR1 engagement is transduced into MAPK signaling, placing MEKK and MEK1 upstream of ERK independent of c-Raf-1/Raf-B.

    Evidence Temporal kinase activity assays and pharmacological dissection in mouse macrophages

    PMID:8933152

    Open questions at the time
    • Single lab, single cell type
    • Direct receptor-to-MEKK linkage not biochemically reconstituted
  3. 1998 High

    Identified a receptor-proximal regulator by showing BRE binds the TNFR1 cytoplasmic domain and dampens TNF-induced NF-κB activation, providing receptor specificity at the signaling interface.

    Evidence Yeast two-hybrid, reciprocal Co-IP and in vitro pulldown, NF-κB reporter assay

    PMID:9737713

    Open questions at the time
    • Mechanism by which BRE inhibits NF-κB not resolved
    • Physiological relevance in primary cells untested
  4. 1999 High

    Demonstrated receptor-specific physiological roles, linking TNFR1 to IRS-1 serine phosphorylation and insulin resistance, and both receptors to Langerhans cell migration.

    Evidence TNF-alpha and receptor knockout mice with phosphorylation/metabolic phenotyping and quantitative migration assays

    PMID:10201952 PMID:10320052

    Open questions at the time
    • Kinase responsible for IRS-1 serine phosphorylation not identified
    • Receptor-specific contributions to migration not fully separated
  5. 2000 High

    Provided the structural basis for TNF-alpha action by defining the homotrimeric ligand and its receptor-binding architecture.

    Evidence X-ray crystal structures of TNF-alpha, TNF-beta, TNFR1 ectodomain, and a TNF-beta/sTNFR-1 complex

    PMID:10891884

    Open questions at the time
    • No structure of full TNF-alpha/TNFR1 or TNFR2 signaling complexes described
    • Transmembrane form not structurally resolved
  6. 2001 High

    Extended TNF-alpha into transcriptional and enzymatic control, showing it represses CD28 transcription in T cells and inhibits 11β-HSD2 via MAPK pathways.

    Evidence EMSA, in vitro transcription and reporter assays in T cells; enzyme activity assays with MEK/ERK and p38 inhibitors in LLC-PK1 cells

    PMID:11544310 PMID:11696370

    Open questions at the time
    • Transcription factors mediating CD28 repression not identified
    • Cell-type generality of 11β-HSD2 effect untested
  7. 2003 High

    Revealed context-dependent and even regenerative/protective outputs: TNF-alpha acts as a satellite-cell mitogen via SRF/SRE and exerts a transient iNOS-dependent antithrombotic effect in the vessel wall.

    Evidence BrdU and SRF-SRE binding assays in myoblasts; intravital microscopy in iNOS- and TNFR-deficient mice

    PMID:12711593 PMID:14617760

    Open questions at the time
    • Receptor mediating satellite-cell mitogenesis not defined
    • Cell type generating iNOS-dependent NO not pinpointed
  8. 2008 High

    Resolved the bifurcation of TNF-alpha-induced caspase-8 activation into a c-FLIP-loss/RIPK1-independent route and a cIAP1/2-degradation/CYLD-dependent RIPK1–FADD–caspase-8 complex, and linked TNFR1 to mitochondrial apoptosis.

    Evidence Orthogonal genetic/pharmacological dissection of cIAP1/2, RIPK1, CYLD, c-FLIP; mitochondrial function and cytochrome c release assays with receptor blockade

    PMID:18485876 PMID:25492727

    Open questions at the time
    • Switch determinants between apoptosis and necroptosis not fully defined
    • Mitochondrial study limited to a single lab/neuronal model
  9. 2010 Medium

    Defined the transmembrane TNF-alpha biology, establishing it as a bidirectional signaling molecule and confirming ADAM17/TACE as the sheddase generating soluble TNF.

    Evidence Review of transmembrane vs soluble construct signaling and metalloprotease cleavage studies

    PMID:20194223

    Open questions at the time
    • Reverse-signaling intracellular effectors not enumerated
    • Review-level synthesis rather than single primary experiment
  10. 2016 High

    Separated RIPK1 scaffold from kinase functions in vivo, showing the scaffold protects hepatocytes from TNF-driven apoptosis while kinase activity drives necrosis.

    Evidence Conditional Ripk1 knockout and kinase-dead knock-in mice in ConA hepatitis

    PMID:27831558

    Open questions at the time
    • Substrate landscape of RIPK1 kinase activity not mapped
    • Tissue specificity beyond liver untested
  11. 2018 Medium

    Connected TNF shedding to disease via iRhom2-controlled ADAM17 activity and revealed transmembrane TNF reverse signaling as a driver of chemoresistance.

    Evidence iRhom2-knockout lupus-prone mice with transcriptome profiling; NTF domain mutants and xenografts for tmTNF reverse signaling

    PMID:29369823 PMID:29559745

    Open questions at the time
    • Direct intracellular partners of the tmTNF intracellular domain not identified
    • iRhom2 specificity for TNF versus other substrates not exhaustive
  12. 2019 Medium

    Linked TNF-alpha to bone resorption through direct osteocyte RANKL induction and identified cortistatin as a competitive antagonist at both receptors.

    Evidence Primary osteocyte/osteoclast co-culture with MAPK inhibitors and in vivo calvarial assays; reciprocal binding assays and receptor-knockout OA models

    PMID:30826358 PMID:31921183

    Open questions at the time
    • Relative receptor contribution to RANKL induction not parsed
    • Cortistatin binding stoichiometry/affinity not quantified
  13. 2020 Medium

    Expanded TNF-alpha's transcriptional reach by identifying MOF-driven H4K16 acetylation as an NF-κB coactivation mechanism and JNK-AP-1-RUNX1 as a distinct endothelial circuit.

    Evidence Myeloid-specific Mof-knockout mice with ChIP and etanercept rescue; pathway-inhibitor dissection in retinal endothelial cells

    PMID:32069267 PMID:33135824

    Open questions at the time
    • Generality of MOF coactivation across inflammatory contexts untested
    • JNK-AP-1-RUNX1 loop shown by inhibitors only, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How cellular context selects among TNF-alpha's divergent outputs — NF-κB survival, apoptosis, necroptosis, regeneration, and metabolic disruption — through a shared receptor set remains unresolved.
  • No unifying quantitative model of TNFR1 versus TNFR2 output selection
  • Structural basis of differential receptor complex assembly not defined
  • Determinants partitioning the RIPK1 complex toward apoptosis versus necroptosis incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
ADAM17BRECSTRHBDF2RIPK1TNFRSF1ATNFRSF1B
Complex memberships
RIPK1-FADD-caspase-8 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TNF-alpha induces two distinct caspase-8 activation pathways: (1) cycloheximide co-treatment promotes caspase-8 activation by eliminating c-FLIP, independent of RIPK1; (2) Smac mimetic triggers autodegradation of cIAP1/2, releasing RIPK1 from the TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8, a process requiring CYLD (a RIPK1 K63 deubiquitinating enzyme). Cell-based signaling assays, pharmacological inhibition (cycloheximide, Smac mimetic), genetic manipulation of cIAP1/2, RIPK1, CYLD, and c-FLIP Cell High 18485876
2000 TNF-alpha acts as a homotrimer that binds to either TNFR1 (55 kDa) or TNFR2 (75 kDa); crystal structures of TNF-alpha, TNF-beta, ectodomain of TNFR1, and the TNF-beta/sTNFR-1 complex have been determined, defining structure-function relationships including cysteine-rich extracellular repeat domains on receptors. X-ray crystallography, structural biology Microscopy research and technique High 10891884
2010 Transmembrane TNF-alpha (tmTNF-alpha) acts as a bipolar molecule: it transmits forward signals as a ligand by binding TNFR1/TNFR2 on target cells, and also acts as a receptor transmitting reverse (outside-to-inside) signals back to the producing cell upon binding of its native receptors. Cell-based signaling assays with transmembrane vs. soluble TNF-alpha constructs; functional differentiation from soluble form via receptor binding studies Rheumatology (Oxford, England) Medium 20194223
2010 Transmembrane TNF-alpha is cleaved from the cell surface by TNF-alpha-converting enzyme (TACE/ADAM17) to generate the soluble form of TNF-alpha. Biochemical cleavage assays; metalloprotease inhibition studies Rheumatology (Oxford, England) Medium 20194223
1995 Matrix metalloproteinases (MMPs) — including stromelysin, matrilysin, collagenase, and gelatinases — can cleave a recombinant pro-TNF substrate to yield mature TNF-alpha in vitro; broad-spectrum MMP inhibitors prevent processing of the TNF precursor and reduce blood TNF levels after endotoxin administration in rats. In vitro cleavage assay with purified MMPs and recombinant pro-TNF substrate; MMP inhibitors in vivo (rat endotoxin model) Journal of leukocyte biology High 7759957
2005 A small-molecule inhibitor of TNF-alpha promotes subunit disassembly of the trimeric cytokine by forming an intermediate complex with the intact trimer, accelerating subunit dissociation 600-fold and leading to a compound-dimer complex. X-ray crystallography revealed a single compound molecule displaces one subunit from the trimer. X-ray crystallography, biochemical dissociation kinetics assay, cell-based inhibition assay Science High 16284179
2001 TNF-alpha promotes oligodendrocyte progenitor proliferation and remyelination through TNFR2 (not TNFR1); mice lacking TNFR2 showed delayed remyelination and reduced pools of proliferating NG2+ oligodendrocyte progenitors and mature oligodendrocytes after cuprizone-induced demyelination. Genetic knockout mice (TNF-alpha-/-, TNFR1-/-, TNFR2-/-), histology, immunohistochemistry, electron microscopy, BrdU labeling Nature neuroscience High 11600888
1999 TNF-alpha mediates insulin resistance through serine phosphorylation of IRS-1, impairing insulin receptor tyrosine phosphorylation signaling; TNF-alpha knockout obese mice showed approximately 2-fold increased insulin-stimulated tyrosine phosphorylation of the insulin receptor in muscle and adipose tissue compared to wild-type obese mice. TNF-alpha and TNF receptor knockout mice (ob/ob background, diet-induced obesity), glucose/insulin tolerance tests, phosphorylation assays Experimental and clinical endocrinology & diabetes High 10320052
1998 BRE protein was identified as a binding partner for the cytoplasmic/juxtamembrane domain of the p55 TNF receptor (TNFR1) via yeast two-hybrid screen and confirmed by in vitro biochemical pulldown with recombinant fusion proteins and co-immunoprecipitation in transfected mammalian cells; BRE specifically interacted with p55 TNFR but not p75 TNFR, Fas, or p75 neurotrophin receptor. Overexpression of BRE inhibited TNF-induced NF-κB activation. Yeast two-hybrid screen, in vitro pulldown with recombinant fusion proteins, co-immunoprecipitation, NF-κB reporter assay FASEB journal High 9737713
1996 TNF-alpha activates the MAPK cascade in macrophages via sequential activation of MEKK and MEK1 in a c-Raf-1- and Raf-B-independent fashion downstream of CD120a (p55 TNFR); MEKK activity peaked within 30 seconds of TNF-alpha exposure, temporally preceding peak activation of p42mapk/ERK2. Kinase activity assays, temporal signaling analysis in mouse macrophages, pharmacological dissection Immunobiology Medium 8933152
2003 In vivo TNF-alpha at sepsis-level doses transiently inhibits thrombus formation via iNOS-dependent generation of NO in the vessel wall; this antithrombotic effect requires iNOS (abolished in iNOS-deficient mice) and is not exerted directly on platelets. TNF receptor 1- and 2-deficient mice showed normal thrombogenesis in the presence of TNF-alpha. Intravital microscopy, iNOS-knockout and TNFR1/TNFR2-deficient mice, platelet function assays, bleeding time measurement Journal of Clinical Investigation High 14617760
1999 TNF-alpha mediates corneal Langerhans cell migration through both TNFR1 (p55) and TNFR2 (p75) signaling; IL-1-induced LC migration is largely mediated by TNFR function, while TNF-alpha-induced LC migration is independent of IL-1 receptor I activity. Gene-targeted knockout mice (IL-1RI-/-, p55-/-, p75-/-, double p55/p75-/-), immunofluorescence migration assay, cytokine injection Journal of immunology High 10201952
2018 iRhom2 regulates ADAM17-dependent shedding of TNF-alpha and HB-EGF; deficiency of iRhom2 simultaneously blocks TNF-alpha and EGFR (HB-EGF) signaling in the kidney, protecting against lupus nephritis without altering anti-dsDNA antibody production. iRhom2-knockout in Fcgr2b-/- lupus-prone mice, transcriptome profiling, pharmacological blockade of TNF-alpha and EGFR Journal of Clinical Investigation High 29369823
2018 Transmembrane TNF-alpha (tmTNF-alpha) mediates doxorubicin resistance in breast cancer cells through reverse signaling via the tmTNF-alpha/NTF-ERK-GST-π axis and tmTNF-alpha/NTF-NF-κB-mediated anti-apoptotic pathways; the intracellular domain of tmTNF-alpha is required, as overexpression of the N-terminal fragment (NTF) containing the intracellular domain was sufficient to induce resistance. tmTNF-alpha overexpression/knockdown, NTF mutant constructs, Western blot, xenograft mouse model Oncogene Medium 29559745
2019 TNF-alpha directly induces RANKL mRNA expression in osteocytes through activation of MAPKs and NF-κB (p65 nuclear translocation), leading to enhanced osteoclastogenesis; MAPK inhibitors significantly decreased TNF-alpha-induced RANKL expression in osteocytes. Primary osteocyte isolation by FACS from Dmp1-Topaz mice, co-culture with TNFR-deficient osteoclast precursors, Western blot for MAPK phosphorylation, in vivo calvarial injection, TRAP staining Frontiers in immunology High 31921183
2016 RIPK1 serves as a scaffold protecting hepatocytes from TNF-alpha-triggered apoptosis; in mice lacking RIPK1 specifically in liver parenchymal cells (Ripk1LPC-KO), ConA-induced hepatitis leads to TNF-alpha-driven massive apoptotic cell death. RIPK1 kinase activity contributes to caspase-independent necrotic cell death. Conditional knockout mice (Ripk1LPC-KO) and RIPK1 kinase-dead knock-in mice (Ripk1K45A), concanavalin A hepatitis model, caspase activity assays Cell death & disease High 27831558
2001 TNF-alpha directly inhibits CD28 gene transcription in T cells by inactivating DNA-protein complex formation at two sequence motifs corresponding to the transcriptional initiator of the CD28 gene; nuclear extracts from TNF-alpha-treated cells failed to activate transcription from templates under control of the CD28 initiator sequences in in vitro transcription assays. Reporter gene assays, electrophoretic mobility shift assay (EMSA), in vitro transcription assay, T cell line/clone culture Journal of immunology High 11544310
2008 TNF-alpha induces mitochondrial dysfunction in neurons through TNFR1 (not TNFR2), involving caspase-8 activation, decrease in mitochondrial membrane potential, and cytochrome c release from mitochondria into the cytosol; pre-treatment with TNFR1 antibody ameliorated neurotoxic effects. Mitochondrial function assays (basal respiration, ATP production), receptor-specific antibody blockade, caspase-8 activity assay, mitochondrial membrane potential measurement, cytochrome c subcellular fractionation Journal of neurochemistry Medium 25492727
2003 TNF-alpha acts as a mitogen in skeletal muscle by activating satellite cells to enter the cell cycle (G1-to-S phase transition) through stimulation of serum response factor (SRF) binding to the serum response element (SRE) in the c-fos gene promoter and activation of early response gene expression. BrdU incorporation assay in primary myoblasts and adult mouse muscle (in vivo injection), SRF-SRE binding assay, reporter gene assay American journal of physiology. Cell physiology Medium 12711593
2015 TNF-alpha suppresses multimerization and secretion of adiponectin by downregulating ER-resident chaperones ERO1-La, DsbA-L, and ERp44, impairing disulfide bond modification; TNF-alpha treatment enhanced the interaction between adiponectin and ERp44. PPARγ overexpression antagonized these effects by directly binding PPRE elements of ERO1-La and DsbA-L promoters. In vitro and in vivo adiponectin multimerization assays, Co-IP (adiponectin-ERp44 interaction), Western blot, ChIP assay for PPARγ binding Endocrine Medium 26407855
2014 TNF-alpha promotes invasive growth by inducing MET receptor tyrosine kinase transcription via NF-κB; MET then sustains MEK/ERK activation and Snail accumulation leading to E-cadherin downregulation. TNF-alpha also induces HGF secretion by fibroblasts, creating a paracrine HGF/MET pro-invasive loop. MET-specific inhibitors (small molecules, antibodies, siRNA), NF-κB pathway analysis, Western blot for Snail and E-cadherin, invasion assays Molecular oncology Medium 25306394
2001 TNF-alpha inhibits 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity and mRNA expression in LLC-PK1 cells via MEK/ERK and p38 MAPK pathways (not PKC), thereby enhancing glucocorticoid access to receptors; the effect was reversed by ERK inhibitor PD-098050, p38 inhibitor SB-202190, or PKA activator forskolin. Overexpression of MEK1 down-regulated 11β-HSD2 activity. Enzyme activity assays, mRNA quantification, kinase inhibitors, MEK1 overexpression, PKC inhibitor GF-109203X FEBS letters Medium 11696370
2018 TNF-alpha induces Drp1-mediated mitochondrial fragmentation in cardiomyocytes through activation of RhoA and the RhoA/ROCK pathway, which phosphorylates Drp1 at Ser616 and promotes its mitochondrial translocation; ROCK inhibitors (Y-27632 and fasudil) attenuated TNF-alpha-induced p-Drp1 Ser616, mitochondrial Drp1 accumulation, and mitochondrial fragmentation. Western blot for Drp1 and p-Drp1 Ser616, confocal microscopy for mitochondrial morphology, ROCK inhibitors, in vitro H9C2 cardiomyocytes International journal of molecular medicine Medium 29336470
2016 TNF-alpha downregulates CIDEC expression in human adipocytes through the MEK/ERK pathway by phosphorylating PPARγ and causing its nuclear export; constitutively active MEK1 mutant recapitulated TNF-alpha effects, and MEK/ERK inhibition prevented TNF-alpha-mediated CIDEC downregulation. Reporter assay confirmed direct reduction in CIDEC transcription. Selective kinase inhibitors, RNAi, constitutively active MEK1 mutant, immunofluorescence, subcellular fractionation, luciferase reporter assay Obesity (Silver Spring) Medium 27062372
2008 TNF-alpha activates Akt and ERK1/2 in premalignant keratinocytes through an atypical protein kinase C (aPKC, zeta/iota-lambda)-, NF-κB-, and hydroxyl radical-dependent pathway; aPKC peptide inhibitor abrogated TNF-alpha effects on Akt and ERK1/2 but increased p38 activation. Iron chelation (blocking OH radical formation) abolished Akt/ERK signaling. Specific peptide inhibitors for aPKC, NF-κB inhibitors, p38 inhibitors, iron chelator desferroxamine, phosphorylation assays in HaCaT cells Experimental dermatology Medium 18557926
2019 Cortistatin (CST) competitively binds to both TNFR1 and TNFR2, suppressing TNF-alpha proinflammatory signaling; CST inhibits NF-κB pathway activation in osteoarthritis, and TNFR1/TNFR2 knockout mice implicated these receptors as required for CST's protective role. Co-immunoprecipitation, biotin-based solid-phase binding assay, Western blot, TNFR1/TNFR2-knockout mice, OA models EBioMedicine Medium 30826358
2002 TNF-alpha mediates skeletal muscle DNA fragmentation (apoptosis) during cancer cachexia; mice deficient in TNFR1 (p55) showed a markedly attenuated increase in muscle DNA fragmentation (2.1-fold vs. 9.8-fold in wild-type) upon Lewis lung carcinoma inoculation. TNF-alpha administration to rats, TNFR1 gene-deficient mice with Lewis lung carcinoma, DNA fragmentation (laddering) assay British journal of cancer Medium 11953838
2020 TNF-alpha stimulates expression of the histone acetyltransferase MOF in macrophages, and MOF acts as a coactivator of NF-κB-mediated inflammatory gene transcription; ChIP showed elevated H4K16 acetylation on inflammatory gene promoters in diabetic wound macrophages; etanercept (TNF-α inhibitor) treatment reduced MOF levels and improved diabetic wound healing. Myeloid-specific Mof-knockout mice (Lyz2Cre Moffl/fl), ChIP for H4K16ac, diet-induced obesity model, etanercept treatment JCI insight Medium 32069267
2011 TNF-alpha (TNFSF2) increases intestinal epithelial paracellular permeability via caspase-driven apoptosis and cell shedding (distinct from IFNγ mechanism which does not involve apoptosis); TNF-alpha also fundamentally alters intestinal epithelial morphogenesis through its pro-apoptotic effect. Infliximab and adalimumab blocked these effects. Three-dimensional intestinal epithelial cell culture system, permeability assays, caspase inhibition, anti-TNF antibody treatment, tight junction protein localization PloS one Medium 21853060
2020 TNF-alpha induces RUNX1 expression in retinal endothelial cells via JNK activation (not NF-κB or p38/MAPK), linking through Activator Protein 1 (AP-1) in a JNK-AP-1-RUNX1 regulatory feedback loop; JNK inhibitors also blocked high D-glucose-stimulated RUNX1 expression. TNF-α pathway inhibitors in HRMECs, Western blot, JNK/NF-κB/p38 inhibitors FASEB journal Medium 33135824

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 TNF-alpha induces two distinct caspase-8 activation pathways. Cell 1138 18485876
2001 TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nature neuroscience 823 11600888
2000 TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microscopy research and technique 806 10891884
2010 Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford, England) 655 20194223
2013 TNF-α signalling and inflammation: interactions between old acquaintances. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 653 23685857
2009 Role of TNF-alpha in vascular dysfunction. Clinical science (London, England : 1979) 554 19118493
2003 Anti-TNF-alpha therapies: the next generation. Nature reviews. Drug discovery 452 12951580
2005 Small-molecule inhibition of TNF-alpha. Science (New York, N.Y.) 426 16284179
1992 TNF alpha--a pivotal role in rheumatoid arthritis? British journal of rheumatology 356 1581770
2014 Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Frontiers in immunology 340 24592264
2001 TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Investigative ophthalmology & visual science 339 11431443
2008 Insulin resistance associated to obesity: the link TNF-alpha. Archives of physiology and biochemistry 333 18629684
1999 The role of TNF alpha in adipocyte metabolism. Seminars in cell & developmental biology 326 10355025
2004 The role of TNF-alpha in insulin resistance. Endocrine 308 15146098
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
2010 TNF-alpha and obesity. Current directions in autoimmunity 252 20173393
2000 TNF-alpha gene polymorphism: clinical and biological implications. Microscopy research and technique 226 10891887
2008 TNF-alpha signaling in glaucomatous neurodegeneration. Progress in brain research 221 18929124
2001 Down-regulation of CD28 expression by TNF-alpha. Journal of immunology (Baltimore, Md. : 1950) 216 11544310
2003 TNF-alpha is a mitogen in skeletal muscle. American journal of physiology. Cell physiology 204 12711593
2019 TNF-α Directly Enhances Osteocyte RANKL Expression and Promotes Osteoclast Formation. Frontiers in immunology 203 31921183
1995 Matrix metalloproteinases and processing of pro-TNF-alpha. Journal of leukocyte biology 202 7759957
2018 Unleashing endogenous TNF-alpha as a cancer immunotherapeutic. Journal of translational medicine 200 30170620
2015 TNF-alpha inhibitors for ankylosing spondylitis. The Cochrane database of systematic reviews 199 25887212
2011 Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS & neurological disorders drug targets 195 21288189
2005 TNF-alpha and pathologic bone resorption. The Keio journal of medicine 179 16237274
2009 TNF-alpha, a potent lipid metabolism regulator. Cell biochemistry and function 167 19757404
2008 Depression, comorbidities and the TNF-alpha system. European psychiatry : the journal of the Association of European Psychiatrists 164 18504118
2000 Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 164 10719836
1998 Sleep. A physiologic role for IL-1 beta and TNF-alpha. Annals of the New York Academy of Sciences 161 9917875
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
2001 TNF-alpha expression in painful and nonpainful neuropathies. Neurology 138 11376190
1992 Tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta). Current opinion in immunology 134 1329840
2020 Complexity of TNF-α Signaling in Heart Disease. Journal of clinical medicine 132 33053859
2008 TNF-alpha as a molecular target in bipolar disorder. Progress in neuro-psychopharmacology & biological psychiatry 127 18316149
2008 TNF-alpha production in the skin. Archives of dermatological research 125 18825399
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
2010 TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Current directions in autoimmunity 96 20173391
2008 The TNF-alpha system: functional aspects in depression, narcolepsy and psychopharmacology. Current neuropharmacology 95 19506720
2009 TNF-alpha in tuberculosis: a cytokine with a split personality. Inflammation & allergy drug targets 94 19275693
2016 TNF-α gene polymorphisms and expression. SpringerPlus 88 27652081
2018 TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness. Journal of experimental & clinical cancer research : CR 83 30591049
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
2024 At the Crossroads of TNF α Signaling and Cancer. Current molecular pharmacology 81 37691196
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
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
2018 Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene 68 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
2015 TNF-α: a treatment target or cause of sarcoidosis? Journal of the European Academy of Dermatology and Venereology : JEADV 64 26419478
2017 TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells. Cancer cell international 63 28127258
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
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 60 21559854
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 58 26407855
2018 TNF-α induces Drp1-mediated mitochondrial fragmentation during inflammatory cardiomyocyte injury. International journal of molecular medicine 54 29336470
2014 TNF-α, a good or bad factor in hematological diseases? Stem cell investigation 54 27358858
2008 Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. Trends in molecular medicine 53 18693138
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
2020 TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF. JCI insight 46 32069267
2013 TNF-α signaling in Fanconi anemia. Blood cells, molecules & diseases 45 23890415
2009 Infliximab and the TNF-alpha system. American journal of physiology. Gastrointestinal and liver physiology 45 19136378
2015 Effects of TNF-α on Cementoblast Differentiation, Mineralization, and Apoptosis. Journal of dental research 44 26088424
2014 TNF-α promotes invasive growth through the MET signaling pathway. Molecular oncology 44 25306394
2007 NRAMP1 and TNF-alpha polymorphisms and susceptibility to tuberculosis in Thais. Respirology (Carlton, Vic.) 44 17298451
2003 TNF-alpha and TNF-beta gene polymorphisms in cerebral infarction. Journal of molecular neuroscience : MN 44 14593215
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
1994 TNF-alpha, the great imitator: role of p55 and p75 TNF receptors in hematopoiesis. Stem cells (Dayton, Ohio) 44 7535144
2022 TNF-α/anti-TNF-α drugs and its effect on pregnancy outcomes. Expert reviews in molecular medicine 43 35687009
2009 IGFBP-3, hypoxia and TNF-alpha inhibit adiponectin transcription. Biochemical and biophysical research communications 43 19324019
2007 Induction of TNF-alpha by LPS in Schwann cell is regulated by MAPK activation signals. Cellular and molecular neurobiology 43 17902045
2019 Targeted TNF-α Overexpression Drives Salivary Gland Inflammation. Journal of dental research 42 30958728
2012 TNF α signaling beholds thalidomide saga: a review of mechanistic role of TNF-α signaling under thalidomide. Current topics in medicinal chemistry 42 22650377
2002 Perspectives for TNF-alpha-targeting therapies. Arthritis research 42 12110119
2001 TNF-alpha enhances intracellular glucocorticoid availability. FEBS letters 42 11696370
2012 TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 41 22487520
2007 The role of soluble TNF receptors for TNF-alpha in uveitis. Investigative ophthalmology & visual science 41 17591895
2020 TNF-α signaling regulates RUNX1 function in endothelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38 33135824
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
2009 TNF-alpha infusion impairs corpora cavernosa reactivity. The journal of sexual medicine 37 19267854
2014 TNF-alpha: a risk factor for ischemic stroke. Journal of Ayub Medical College, Abbottabad : JAMC 36 25603656
2008 TNF-alpha stimulates Akt by a distinct aPKC-dependent pathway in premalignant keratinocytes. Experimental dermatology 36 18557926
2020 TNF-α-induced p53 activation induces apoptosis in neurological injury. Journal of cellular and molecular medicine 34 32344470
2014 TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats. American journal of physiology. Renal physiology 34 25391899
2011 Differential effects of TNF (TNFSF2) and IFN-γ on intestinal epithelial cell morphogenesis and barrier function in three-dimensional culture. PloS one 34 21853060
2016 TNF-α downregulates CIDEC via MEK/ERK pathway in human adipocytes. Obesity (Silver Spring, Md.) 33 27062372

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