Affinage

TNFSF12

Tumor necrosis factor ligand superfamily member 12 · UniProt O43508

Length
249 aa
Mass
27.2 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF12 (TWEAK) is a TNF superfamily cytokine that functions as a pleiotropic regulator of inflammation, tissue repair, cell death, and proliferation through engagement of its receptor Fn14 (TNFRSF12A). TWEAK exists as a membrane-anchored form processed intracellularly by furin at residues 90–93 and as a soluble form scavenged by the decoy receptor CD163; membrane TWEAK signals in a juxtacrine manner, while soluble TWEAK acts at a distance, with both forms activating canonical (IκBα/RelA/p50) and noncanonical (NIK/IKK1/p100→p52/RelB) NF-κB pathways through TRAF1/2/3 recruitment to the Fn14 cytoplasmic domain (PMID:11728344, PMID:12840022, PMID:20385556, PMID:26242746). Beyond NF-κB, TWEAK/Fn14 transactivates EGFR via ADAM17-mediated shedding of HB-EGF and TGFα to drive ERK-dependent inflammatory gene expression, activates PI3K–Akt and MAPK–ERK cascades regulating cell cycle progression, and epigenetically silences protective genes including Klotho and PGC-1α through RelA-directed histone deacetylation at their promoters (PMID:24037740, PMID:21719790, PMID:26535995, PMID:31395500). These signaling outputs underlie context-dependent biological activities: stimulation of progenitor and myoblast proliferation and fusion via noncanonical NF-κB, induction of cathepsin B–dependent necrosis or caspase-dependent apoptosis, RIPK1/RIPK3/MLKL-dependent necroptosis in renal tubular cells during acute kidney injury, promotion of epithelial–mesenchymal transition driving colorectal cancer metastasis, and pro-fibrotic remodeling in cardiac tissue through the adaptor TRAF3IP2 (PMID:23074266, PMID:11777967, PMID:29588419, PMID:38335276, PMID:29981796).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing that TWEAK is a monocyte-surface cytokine and ruling out DR3 as its receptor resolved a receptor-identity question that had complicated the field since TWEAK's cloning.

    Evidence Flow cytometry on IFN-γ-stimulated monocytes with anti-TWEAK mAb blocking; DR3-KO mouse cells retaining TWEAK binding

    PMID:11067885 PMID:11094155

    Open questions at the time
    • Identity of the true TWEAK receptor was still unknown
    • Signaling pathways downstream of TWEAK binding uncharacterized
  2. 2001 High

    Identification of Fn14 as the bona fide TWEAK receptor with 2.3 nM affinity and TRAF1/2/3 recruitment established the ligand–receptor pair and immediately linked it to angiogenesis and endothelial growth.

    Evidence Receptor cloning from HUVEC library, saturation binding, Co-IP/pulldown for TRAF binding, corneal angiogenesis model

    PMID:11728344

    Open questions at the time
    • Which NF-κB pathways are activated downstream of TRAF recruitment was unresolved
    • Relative roles of membrane vs. soluble TWEAK unknown
  3. 2002 High

    Dissection of TWEAK-induced cell death revealed that it operates through at least three distinct mechanisms — caspase-dependent apoptosis, cathepsin B-dependent necrosis, and indirect TNF-α-mediated killing — establishing TWEAK as a context-dependent death ligand.

    Evidence Caspase/cathepsin B inhibitors, lysosomal fractionation, anti-TNF-α blocking in multiple cell lines

    PMID:11777967

    Open questions at the time
    • Receptor mediating TWEAK death signaling not yet confirmed as Fn14
    • Necroptotic pathway not yet explored
  4. 2003 High

    Demonstration that TWEAK/Fn14 sequentially activates both canonical (NEMO-dependent, rapid IκBα phosphorylation) and noncanonical (IKK1/NIK-dependent p100 processing) NF-κB defined the dual signaling architecture downstream of Fn14.

    Evidence TRAF-binding site mutagenesis, TRAF2/TRAF5-KO cells, proteasome inhibitor studies, EMSA

    PMID:12840022

    Open questions at the time
    • Cell-type-specific dominance of canonical vs. noncanonical pathways undetermined
    • Non-NF-κB signaling arms not yet mapped
  5. 2005 High

    Showing that TWEAK/Fn14 selectively drives liver progenitor (oval) cell proliferation in vivo provided the first genetic evidence that TWEAK acts as a tissue-repair mitogen for progenitor populations.

    Evidence Fn14-KO mice, TWEAK-transgenic and adenoviral overexpression, anti-TWEAK mAb, DDC injury model

    PMID:16110324

    Open questions at the time
    • Downstream signaling pathway mediating oval cell proliferation not fully resolved
    • Whether TWEAK drives other stem/progenitor compartments unknown
  6. 2006 High

    Extension to myoblasts and osteoblasts revealed that TWEAK/Fn14 broadly controls mesenchymal progenitor proliferation and differentiation, engaging PI3K–Akt and MAPK–ERK in addition to NF-κB depending on cell type.

    Evidence Fn14-KO primary myoblasts, C2C12 differentiation, cardiotoxin injury model, PI3K/ERK inhibitors in osteoblasts

    PMID:16945157 PMID:17124496

    Open questions at the time
    • Mechanism by which TWEAK inhibits osteoblast differentiation vs. promoting myoblast proliferation not reconciled
    • Relative contribution of canonical vs. noncanonical NF-κB to myoblast phenotype unclear
  7. 2008 High

    In vivo renal studies established that TWEAK/Fn14 drives tubular NF-κB activation, chemokine production, and macrophage infiltration, positioning the axis as a central mediator of kidney inflammatory injury.

    Evidence Systemic TWEAK administration in mice, anti-TWEAK mAb in folic acid AKI, parthenolide NF-κB inhibition

    PMID:18235096

    Open questions at the time
    • Direct vs. indirect effects on macrophage recruitment not separated
    • Whether non-NF-κB pathways contribute to renal injury not explored
  8. 2010 High

    Identification of furin cleavage at residues 90–93 and demonstration that uncleaved membrane TWEAK signals in trans via juxtacrine Fn14 engagement resolved how TWEAK exists in two functional forms.

    Evidence Furin cleavage-site mutagenesis, furin inhibitor, co-culture NF-κB reporter assays

    PMID:20385556

    Open questions at the time
    • Whether other proteases contribute to shedding in specific tissues unknown
    • Relative potency of membrane vs. soluble TWEAK in vivo not quantified
  9. 2011 High

    Discovery that TWEAK epigenetically silences renal Klotho via RelA binding and histone deacetylation at its promoter revealed a chromatin-level mechanism by which TWEAK accelerates kidney aging/injury phenotypes.

    Evidence ChIP showing RelA at Klotho promoter, HDAC inhibitor rescue, TWEAK-KO mice, anti-TWEAK in folic acid AKI

    PMID:21719790

    Open questions at the time
    • Which specific HDAC is recruited not identified
    • Whether Klotho downregulation is the primary driver of renal pathology vs. a parallel effect unclear
  10. 2012 High

    Selective genetic dissection showed that low-dose TWEAK promotes myoblast fusion specifically through the noncanonical NF-κB pathway (p100/RelB/IKKα/NIK), while high-dose TWEAK engages canonical NF-κB causing atrophy, resolving a dose-dependent signaling paradox.

    Evidence cIAP1-KO, siRNA of p100/RelB/IKKα/NIK/TRAF3, p52/RelB overexpression, myotube fusion assays

    PMID:23074266

    Open questions at the time
    • In vivo confirmation of dose-dependent pathway switching not performed
    • Whether cIAP1 degradation is a physiological TWEAK-triggered event unclear
  11. 2013 High

    Identification of ADAM17-mediated EGFR transactivation as an EGFR-dependent, NF-κB-independent arm of TWEAK signaling revealed a second major effector pathway that drives ERK-dependent inflammation through HB-EGF and TGFα shedding.

    Evidence ADAM17 inhibitor, erlotinib, EGFR phosphorylation assays, in vivo TWEAK administration

    PMID:24037740

    Open questions at the time
    • Whether EGFR transactivation occurs in non-renal tissues unknown
    • Direct mechanism linking Fn14 to ADAM17 activation not defined
  12. 2015 High

    Establishing CD163 as a decoy/scavenger receptor for soluble TWEAK explained how macrophage phenotype regulates TWEAK bioavailability and muscle progenitor cell responses during ischemia.

    Evidence CD163-KO mice with elevated TWEAK and enhanced satellite cell proliferation, binding assays, ischemic injury model

    PMID:19473660 PMID:26242746

    Open questions at the time
    • Whether CD163 signals upon TWEAK binding or is purely a decoy not resolved
    • Contribution of CD163-TWEAK axis in non-muscle tissues not explored
  13. 2016 High

    Extension of the epigenetic silencing mechanism to PGC-1α — via NF-κB-driven histone deacetylation at its promoter — linked TWEAK to mitochondrial dysfunction in both muscle and kidney, unifying metabolic and inflammatory consequences of sustained TWEAK signaling.

    Evidence ChIP at PGC-1α promoter, HDAC/NF-κB inhibitors, adenoviral PGC-1α rescue, TWEAK-KO/Fn14-KO mice denervation model

    PMID:24327607 PMID:26535995

    Open questions at the time
    • Identity of the recruited HDAC enzyme not determined
    • Whether TWEAK affects other metabolic gene promoters via the same mechanism unknown
  14. 2018 High

    Demonstration that TWEAK/Fn14 triggers RIPK1/RIPK3/MLKL-dependent necroptosis as a temporally distinct late wave of tubular cell death in AKI established necroptosis as a TWEAK-mediated death modality and explained why caspase inhibition alone is insufficient for renal protection.

    Evidence Necrostatin-1, RIPK3-deficient and MLKL-deficient mice, Fn14-KO, folic acid AKI with temporal dissection

    PMID:29588419

    Open questions at the time
    • Whether TWEAK directly activates RIPK1 or does so via TNF-α co-signaling not fully resolved
    • Upstream signals determining apoptosis vs. necroptosis switching remain unclear
  15. 2018 High

    Identification of TRAF3IP2 as a required adaptor for TWEAK-induced cardiac fibrosis — mediating p38 MAPK, NF-κB, and AP-1 activation — revealed a tissue-specific signaling node in fibroblasts.

    Evidence TRAF3IP2-KO mice, siRNA in cardiac fibroblasts, TWEAK infusion, collagen/MMP readouts

    PMID:29981796

    Open questions at the time
    • How TRAF3IP2 is recruited to the Fn14 signaling complex not determined
    • Whether TRAF3IP2 participates in TWEAK signaling in non-cardiac fibroblasts unknown
  16. 2019 High

    Mechanistic dissection of VSMC proliferation showed TWEAK drives cell cycle progression via ERK/Akt-dependent cyclin D1–CDK4/6 upregulation and p15INK4B suppression, explaining TWEAK's pro-neointimal role after vascular injury.

    Evidence Tnfrsf12a/Tnfsf12-KO VSMCs, wire injury model, anti-TWEAK mAb, ERK/Akt inhibitors, NGS

    PMID:31395500

    Open questions at the time
    • Whether noncanonical NF-κB contributes to VSMC phenotype not tested
    • Relevance to human restenosis not established
  17. 2021 High

    TWEAK/Fn14 was shown to synergize with TNF and IL-17A in keratinocytes to amplify psoriasis-signature gene expression, and keratinocyte-specific Fn14 deletion protected against psoriasiform inflammation, establishing TWEAK as a co-driver of skin autoimmunity.

    Evidence Keratinocyte-specific Fn14-KO mice, imiquimod model, transcriptomics, miR-149 target validation for Fn14

    PMID:33705829 PMID:34797693

    Open questions at the time
    • Whether TWEAK blockade is therapeutically effective in human psoriasis untested
    • Mechanism of TWEAK synergy with IL-17A at the promoter level not defined
  18. 2024 High

    Th17-derived TWEAK was identified as a driver of colorectal cancer liver metastasis through Fn14-dependent EMT, demonstrating a tumor-extrinsic immune source of TWEAK that promotes cancer dissemination.

    Evidence scRNA-seq, CRISPR Fn14-KO tumor cells, Tnfsf12-KO mice, Th17 cotransfer experiments, EMT marker analysis

    PMID:38335276

    Open questions at the time
    • Whether TWEAK-induced EMT is reversible upon Fn14 blockade not addressed
    • Applicability beyond colorectal cancer not explored
    • Contribution of other Th17 cytokines confounding in cotransfer experiments

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of Fn14 signaling complex assembly, the identity of HDACs recruited to TWEAK-silenced promoters, the molecular switch determining whether TWEAK triggers apoptosis, necroptosis, or proliferation in a given cell, and the therapeutic window for TWEAK/Fn14 blockade in human disease.
  • No crystal structure of TWEAK–Fn14 signaling complex available
  • HDAC identity at Klotho and PGC-1α promoters not determined
  • Dose- and context-dependent pathway switching mechanism not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1643685 Disease 2
Partners
ADAM17CD163GSK3BTNFRSF12ATRAF1TRAF2TRAF3TRAF3IP2

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TWEAK (TNFSF12) binds to TweakR/Fn14, a small TNF receptor family member cloned from HUVEC library, with an affinity constant Kd of 2.3 ± 0.1 nM; the TweakR cytoplasmic domain binds TRAF1, TRAF2, and TRAF3; cross-linking of TweakR induces HUVEC growth; soluble TweakR inhibits endothelial cell migration and corneal angiogenesis in vivo. Five binding assays including receptor cloning, affinity measurement, Co-IP/pulldown for TRAF binding, HUVEC growth assay, corneal angiogenesis model Immunity High 11728344
2003 TWEAK sequentially activates two NF-κB cascades: (1) rapid IκBα phosphorylation generating p50/RelA complexes via canonical IKK complex (NEMO-dependent); (2) prolonged activation via proteasome-mediated NF-κB2/p100 processing generating RelB complexes (NEMO-independent, requiring IKK1 and NF-κB-inducing kinase). Fn14 with mutated TRAF-binding site cannot activate NF-κB; cells deficient in TRAF2 and TRAF5 fail to show p100 processing and IκBα phosphorylation. Expression cloning, IκBα phosphorylation assays, EMSA, TRAF-binding site mutagenesis, TRAF2/TRAF5 knockout cells, proteasome inhibitor studies The Journal of biological chemistry High 12840022
2002 TWEAK-induced cell death occurs through multiple pathways: caspase-8 and caspase-3-dependent apoptosis in HSC3 cells; cathepsin B-dependent necrosis (with lysosomal cathepsin B release to cytosol) in IFN-γ-treated HT-29 cells; and indirect TNF-α-mediated cell death in Kym-1 cells. DR3 is not the relevant receptor as TWEAK-sensitive cell lines do not express DR3 but bind TWEAK via a distinct receptor. Caspase activity assays, pan-caspase inhibitors, cathepsin B inhibitors, lysosomal fractionation, anti-TNF-α blocking antibodies, DR3 expression analysis by Western blot and RT-PCR Journal of immunology High 11777967
2000 TWEAK is expressed on the surface of IFN-γ-stimulated monocytes (but not IFN-α or LPS-stimulated) and mediates cytotoxic killing of tumor cells; anti-TWEAK mAb partially inhibited monocyte cytotoxicity, with near-complete inhibition in combination with anti-TRAIL. Anti-human TWEAK mAb generation, flow cytometry, cytotoxicity assays with neutralizing antibodies The Journal of experimental medicine High 11067885
2000 TWEAK and DR3/WSL-1/TRAMP do not interact in in vitro binding assays; TWEAK binds to cells lacking DR3 surface expression and shows biological activity there; cells from DR3 knockout mice retain TWEAK-binding capacity, demonstrating DR3 is not the major TWEAK receptor. In vitro binding assay, flow cytometry, DR3 knockout mouse cells FEBS letters High 11094155
2002 An endogenous hybrid mRNA (TWE-PRIL) encodes a fusion protein composed of TWEAK cytoplasmic and transmembrane domains fused to the APRIL C-terminal receptor-binding domain; TWE-PRIL is membrane-anchored, presents APRIL's receptor-binding domain at the cell surface, and is biologically active (stimulates cycling in T- and B-lymphoma cell lines). Detected in primary human T lymphocytes and monocytic cell lines by RACE, RT-PCR, cDNA library screening, RNase protection assay. RACE, RT-PCR, cDNA library screening, RNase protection assay, flow cytometry, proliferation assay The EMBO journal High 12411489
2005 TWEAK selectively stimulates liver progenitor (oval) cell proliferation via its receptor Fn14; transgenic TWEAK overexpression in hepatocytes causes oval cell hyperplasia; TWEAK-adenovirus induced oval cell expansion in WT but not Fn14-null mice; DDC-induced oval cell expansion was reduced in Fn14-null mice and by anti-TWEAK mAb; TWEAK stimulated proliferation of oval cell cultures directly. Transgenic overexpression, adenoviral delivery, Fn14 knockout mice, blocking anti-TWEAK mAb, DDC injury model, cell culture proliferation assays The Journal of clinical investigation High 16110324
2006 TWEAK binds to mesenchymal progenitor cells (all lineages) and induces NF-κB activation, pro-survival, pro-proliferative and homing receptor gene expression. TWEAK promotes C2C12 myoblast proliferation and inhibits terminal differentiation. Fn14-deficient primary myoblasts show reduced proliferative capacity and altered myotube formation. After cardiotoxin injury, Fn14-deficient mice show reduced inflammatory response and delayed muscle fiber regeneration. Cell binding assays, NF-κB reporter assays, Fn14 knockout mice, C2C12 and primary myoblast proliferation/differentiation assays, cardiotoxin muscle injury model The EMBO journal High 17124496
2008 TWEAK induces NF-κB activation in tubular epithelial cells (MCT line) via IκBα degradation and RelA nuclear translocation, leading to increased MCP-1, RANTES, and IL-6 expression. In vivo systemic TWEAK administration induces renal NF-κB activation, chemokine expression and interstitial inflammation; neutralization of TWEAK with blocking antibody reduces tubular chemokine expression and macrophage infiltration after folic acid-induced AKI. Parthenolide (IκBα degradation inhibitor) blocked all TWEAK-induced effects. In vitro NF-κB activation assays, Western blot for IκBα, nuclear translocation assays, ELISA, in vivo TWEAK administration in mice, anti-TWEAK mAb neutralization, folic acid AKI model Journal of the American Society of Nephrology High 18235096
2010 Full-length human TWEAK is processed intracellularly by the serine protease furin at amino acid residues 90–93 (the predominant furin recognition site). Full-length, membrane-anchored TWEAK can bind Fn14 on neighboring cells (juxtacrine signaling) and activate the NF-κB signaling pathway. Furin inhibitor studies, site-directed mutagenesis of furin cleavage site, co-culture assays, NF-κB reporter assays The Journal of biological chemistry High 20385556
2006 TWEAK/Fn14 interaction in osteoblastic MC3T3-E1 cells induces RANTES via PI3K-Akt (not NF-κB); inhibits BMP-2-induced osteoblast differentiation markers via MAPK-ERK; and upregulates RANKL expression via MAPK-ERK pathway. All effects abolished by Fn14-Fc chimera decoy receptor. PI3K inhibitors, ERK inhibitors, MAPK pathway analysis, BMP-2 differentiation assays, RANKL expression measurement, Fn14-Fc neutralization Arthritis research & therapy Medium 16945157
2011 TWEAK and TNFα reduce renal Klotho expression through NF-κB-dependent mechanism. TWEAK promotes RelA binding to the Klotho promoter and induces histone deacetylation of the Klotho promoter. NF-κB inhibitor parthenolide and histone deacetylase inhibitor both prevent TWEAK-induced Klotho downregulation. Confirmed in vivo: TWEAK blockade or genetic absence abrogated injury-related decrease in renal Klotho. siRNA knockdown of IκBα, parthenolide NF-κB inhibition, HDAC inhibitor, chromatin immunoprecipitation (ChIP), TWEAK knockout mice, anti-TWEAK antibody in folic acid AKI model Journal of the American Society of Nephrology High 21719790
2012 TWEAK activates the noncanonical NF-κB pathway (through p100 processing, RelB, IKKα, and NIK) to promote myoblast fusion into multinucleated myotubes. Loss of cIAP1 leads to constitutive noncanonical NF-κB activation and increased myotube nuclei. Low-dose TWEAK, which preferentially activates the noncanonical pathway, increases myoblast fusion without causing atrophy. cIAP1 knockout, siRNA knockdown of p100/RelB/IKKα/NIK/TRAF3, p52/RelB overexpression, NF-κB reporter assays, myotube fusion quantification Science signaling High 23074266
2013 TWEAK transactivates EGFR in renal tubular epithelial cells via Fn14-dependent ADAM17 activation and subsequent release of EGFR ligands HB-EGF and TGFα. TWEAK-induced proinflammatory factor expression and ERK activation require EGFR signaling (blocked by erlotinib or ADAM17 inhibitor), while TWEAK-mediated NF-κB activation is EGFR-independent. EGFR phosphorylation assays, ADAM17 inhibitor (WTACE-2), EGFR kinase inhibitor (erlotinib), in vivo TWEAK administration in mice, HB-EGF/TGFα measurement The Journal of pathology High 24037740
2015 CD163 functions as a decoy receptor for soluble TWEAK during ischemia; soluble CD163 sequesters TWEAK and inhibits TWEAK-induced canonical NF-κB and Notch signaling required for myogenic progenitor cell proliferation. CD163-knockout mice have transiently elevated TWEAK levels, stimulating muscle satellite cell proliferation and tissue regeneration. CD163 knockout mice, soluble TWEAK binding assays, NF-κB and Notch signaling assays, ischemic injury model, macrophage internalization experiments Nature communications High 26242746
2009 CD163-expressing macrophages can bind and internalize TWEAK protein (demonstrated in vitro with exogenously added TWEAK from supernatants), suggesting CD163 is a scavenger receptor for TWEAK. In vitro TWEAK binding and internalization assay with CD163-expressing macrophages Atherosclerosis Medium 19473660
2013 TWEAK/Fn14 signaling regulates skeletal muscle PGC-1α levels: TWEAK reduces PGC-1α and mitochondrial content (~50%) in skeletal muscle. PGC-1α levels are significantly increased in TWEAK-KO and Fn14-KO mice upon denervation. Transgenic PGC-1α overexpression inhibits muscle wasting in TWEAK-Tg mice, inhibits TWEAK-induced NF-κB activation (~50%), reduces atrogene (MAFbx, MuRF1) expression (~90%), and prevents Fn14 induction in denervated muscle. TWEAK-KO and Fn14-KO mice, TWEAK-Tg mice, PGC-1α Tg overexpression, denervation model, NF-κB activation assays, atrogene expression measurement, mitochondrial content quantification FASEB journal High 24327607
2016 TWEAK decreases PGC-1α expression in tubular cells via NF-κB-dependent histone H3 deacetylation at the PGC-1α promoter, leading to decreased expression of PGC-1α target genes and reduced mitochondrial membrane potential. HDAC inhibitors and NF-κB inhibitors both prevent TWEAK-induced PGC-1α downregulation. Adenoviral PGC-1α overexpression rescues TWEAK-induced mitochondrial dysfunction. Chromatin immunoprecipitation (histone deacetylation at PGC-1α promoter), NF-κB inhibitors, HDAC inhibitors, adenoviral PGC-1α overexpression, mitochondrial membrane potential assays, neutralizing anti-TWEAK antibodies in folic acid AKI Kidney international High 26535995
2018 TWEAK/Fn14 activation drives a second wave of tubular cell death during AKI through necroptosis. In cultured tubular cells, TWEAK induces apoptosis in a proinflammatory environment; caspase inhibition switches this to necroptosis. In folic acid AKI mice, Fn14 ablation and RIPK1 inhibition (Nec-1) or RIPK3/MLKL deficiency protect against a late (72–96 h) wave of cell death and kidney dysfunction, but not early (48 h) cell death. Necrostatin-1 (RIPK1 inhibitor), genetic RIPK3 deficiency, MLKL deficiency, Fn14 genetic ablation, caspase inhibitors, folic acid AKI model, tubular cell culture with TWEAK treatment Proceedings of the National Academy of Sciences High 29588419
2018 TRAF3IP2 mediates TWEAK/Fn14 pro-fibrotic signaling in cardiac fibroblasts: exogenous TWEAK upregulates TRAF3IP2 in a time- and dose-dependent manner (positive feedback), and TWEAK promotes TRAF3IP2 nuclear translocation. Silencing TRAF3IP2 inhibits TWEAK-induced p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP activation, collagen synthesis, and CF proliferation/migration. Genetic TRAF3IP2 ablation in vivo blocks TWEAK-induced cardiac fibrosis and dysfunction. TRAF3IP2 overexpression and siRNA knockdown in cardiac fibroblasts, p38 MAPK/NF-κB/AP-1 activation assays, collagen secretion assays, TWEAK infusion in mice, TRAF3IP2 knockout mice Journal of molecular and cellular cardiology High 29981796
2004 A short variant of TWEAK (shortTWEAK) forms a complex with GSK-3β in a yeast two-hybrid system and colocalizes with GSK-3β in the nucleus of neuroblastoma cells. TWEAK is internalized and translocates to the nucleus, causing IκBα degradation, nuclear translocation of both GSK-3β and p65, and NF-κB-driven gene expression. LiCl (GSK-3β inhibitor) counteracts TWEAK-induced IL-8 expression. Yeast two-hybrid, colocalization by immunofluorescence, TWEAK internalization assay, NF-κB reporter assays, LiCl inhibition of GSK-3β FEBS letters Medium 15147869
2019 TWEAK/Fn14 signaling drives VSMC proliferation and migration through upregulation of cyclins D1, CDK4/CDK6, and downregulation of CDK inhibitor p15INK4B via ERK and Akt activation. Genetic depletion of Tnfrsf12a or Tnfsf12 and pharmacological anti-TWEAK antibody reduce neointimal formation, cell proliferation, cyclin D1/CDK4/6, and increase p15INK4B in wire-injured mouse femoral arteries. Next-generation sequencing of TWEAK-regulated genes, Tnfrsf12a/Tnfsf12 knockout VSMCs, wound-healing/Transwell migration assays, cyclin/CDK expression by Western blot, wire injury mouse model, anti-TWEAK mAb treatment, ERK/Akt inhibition EBioMedicine High 31395500
2012 TWEAK/Fn14 activates NF-κB in cardiac fibroblasts, increasing MMP-9 production and promoting CF proliferation and collagen synthesis; siRNA knockdown of Fn14 or NF-κB inhibitor (PDTC) prevents these effects. Fn14 siRNA knockdown, PDTC NF-κB inhibition, MMP-9 activity assay, collagen synthesis measurement, CF proliferation assays Molecular biology reports Medium 22555979
2021 In keratinocytes, IFN-γ suppresses miR-149, and the TWEAK receptor Fn14 is a direct target of miR-149 (validated by 3'UTR reporter assays). IFN-γ-mediated miR-149 suppression amplifies keratinocyte inflammatory responses to TWEAK; synthetic miR-149 overexpression is protective in imiquimod-induced psoriasis mouse model. miR-149 target validation (reporter assays), miR-149 overexpression/inhibition in keratinocytes, intradermal miR-149 injection in mice, imiquimod psoriasis model The Journal of allergy and clinical immunology Medium 33705829
2021 In keratinocytes, TWEAK/Fn14 signaling synergizes with TNF and IL-17A to upregulate psoriasis-signature genes (CXC chemokines, IL-23A, IL-36G, S100A8/9, SERPINB1/B9). Keratinocyte-specific deletion of Fn14 reduces imiquimod-induced skin inflammation, epidermal hyperplasia, and psoriasis gene expression. Keratinocyte-specific Fn14 knockout mice, transcriptomic analysis in human keratinocytes, anti-TWEAK therapeutic treatment, imiquimod psoriasis model, combination cytokine stimulation assays Science immunology High 34797693
2018 TWEAK/Fn14 signaling mediates HL-1 atrial myocyte hypertrophy through the JAK2/STAT3 pathway: TWEAK increases ANP and Troponin T expression, Fn14 knockdown blocks these effects, and siRNA inhibition of JAK2 or STAT3 attenuates TWEAK-induced hypertrophy. Fn14 knockdown, JAK2/STAT3 siRNA, hypertrophy markers (ANP, Troponin T) measurement in HL-1 atrial myocytes Journal of cellular and molecular medicine Medium 29971943
2016 TWEAK upregulates ECE-1 (endothelin-converting enzyme-1) and ET-1 production in endothelial cells via AP-1 (through ERK1/2 and JNK) and NF-κB transcription factors acting on the ECE-1 promoter. Both AP-1 and NF-κB inhibitors partially block the effect. Validated in vivo: TWEAK injection in mice increases aortic and lung ECE-1 and ET-1 expression. ECE-1 promoter deletion/transfection assays, EMSA for AP-1 and NF-κB, ERK/JNK inhibitors, NF-κB inhibitor, in vivo TWEAK injection in mice, Western blot and qPCR, ET-1 ELISA Cardiovascular research Medium 28025386
2024 TWEAK secreted by Th17 cells promotes epithelial-mesenchymal transition (EMT) in colorectal cancer cells by binding to Fn14 on tumor cells, enhancing tumor migration and invasion. In mouse models, Fn14 knockout (CRISPR) or Tnfsf12 deletion reduces liver metastases and prolongs survival. Cotransfer of Th17 cells with tumor cells promotes liver metastasis. Single-cell RNA sequencing, CRISPR-mediated Fn14 knockout, Tnfsf12 knockout mice, LNP-encapsulated siRNA, Il17a knockout mice, Th17 cotransfer experiments, EMT markers Cancer research High 38335276
2011 IL-13-induced apoptosis (caspase-3 activation) in intestinal epithelial explants requires TWEAK, Fn14, and endogenous TNF-α secreted via ADAM17. Conversely, TNF-α-induced caspase activation requires IL-13, TWEAK, and Fn14. This was demonstrated using intestinal explants from TWEAK knockout mice. TWEAK knockout mice intestinal explants, ADAM17 inhibition, caspase-3 activation assays, IL-13 and TNF-α treatments Gastroenterology High 21893119
2021 TWEAK administration induces cystogenesis and worsens the ADPKD phenotype; anti-TWEAK antibodies slow cystic progression and preserve renal function. The anti-cystogenic effect is associated with decreased MAPK signaling (cell proliferation-related), decreased NF-κB pathway activation, reduced fibrosis and apoptosis, and indirect decrease of macrophage recruitment. TWEAK administration in murine ADPKD model, anti-TWEAK antibody treatment, MAPK/NF-κB signaling assays, macrophage infiltration quantification, survival analysis Journal of the American Society of Nephrology Medium 34155062

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nature reviews. Drug discovery 492 18404150
2011 The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. Journal of the American Society of Nephrology : JASN 343 21719790
2005 TWEAK induces liver progenitor cell proliferation. The Journal of clinical investigation 334 16110324
2001 A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 327 11728344
2003 TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. The Journal of biological chemistry 277 12840022
2003 TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine & growth factor reviews 253 12787562
2007 TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 244 17981048
2006 TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. The EMBO journal 192 17124496
2008 The cytokine TWEAK modulates renal tubulointerstitial inflammation. Journal of the American Society of Nephrology : JASN 164 18235096
2002 Multiple pathways of TWEAK-induced cell death. Journal of immunology (Baltimore, Md. : 1950) 148 11777967
2000 Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity. The Journal of experimental medicine 146 11067885
2006 Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. Journal of immunology (Baltimore, Md. : 1950) 139 16424220
2018 TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proceedings of the National Academy of Sciences of the United States of America 129 29588419
2009 The CD163-expressing macrophages recognize and internalize TWEAK: potential consequences in atherosclerosis. Atherosclerosis 124 19473660
2004 TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages. Circulation journal : official journal of the Japanese Circulation Society 123 15056843
2002 An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. The EMBO journal 117 12411489
2016 The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney international 116 26535995
2002 Dual role for TWEAK in angiogenic regulation. Journal of cell science 108 11839778
2000 TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. Journal of immunology (Baltimore, Md. : 1950) 108 10706675
2008 Additive effects of soluble TWEAK and inflammation on mortality in hemodialysis patients. Clinical journal of the American Society of Nephrology : CJASN 100 18945991
2004 The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Frontiers in bioscience : a journal and virtual library 97 15353286
2012 Role of TWEAK in lupus nephritis: a bench-to-bedside review. Journal of autoimmunity 95 22727560
2015 CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury. Nature communications 91 26242746
2017 Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. Cell calcium 86 28619231
2012 Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis. Clinical immunology (Orlando, Fla.) 86 22982296
2011 Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes. Clinical journal of the American Society of Nephrology : CJASN 85 21330486
2017 Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development. International journal of molecular sciences 83 28809783
2013 Neuropsychiatric Lupus, the Blood Brain Barrier, and the TWEAK/Fn14 Pathway. Frontiers in immunology 80 24400009
2021 TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy. Science immunology 77 34797693
2011 Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 74 21893119
2012 TWEAK and cIAP1 regulate myoblast fusion through the noncanonical NF-κB signaling pathway. Science signaling 70 23074266
2017 TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis. Nature communications 68 28530223
2010 Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms. Clinical cancer research : an official journal of the American Association for Cancer Research 65 20068083
2010 Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway. The Journal of biological chemistry 65 20385556
2013 TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. Journal of neuroinflammation 64 23320797
2015 The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 62 26300004
2006 TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells. Arthritis research & therapy 61 16945157
2014 TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction. Frontiers in immunology 60 24478779
2013 Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 24327607
2024 Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis. Cancer research 58 38335276
2013 The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease. Cytokine & growth factor reviews 58 24444596
2008 No end in site: TWEAK/Fn14 activation and autoimmunity associated- end-organ pathologies. Journal of leukocyte biology 58 18483204
2012 The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases. Journal of leukocyte biology 56 22672874
2021 The TWEAK/Fn14/CD163 axis-implications for metabolic disease. Reviews in endocrine & metabolic disorders 55 34542797
2020 TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. Journal of hepatology 55 33221352
2017 TWEAK/Fn14 signaling in tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 55 28639899
2009 Considering TWEAK as a target for therapy in renal and vascular injury. Cytokine & growth factor reviews 53 19482507
2012 TWEAK/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-кB pathway. Molecular biology reports 52 22555979
2000 Down-regulated expression of TWEAK mRNA in acute and chronic inflammatory pathologies. Biochemical and biophysical research communications 52 11112433
2003 Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Biochemical and biophysical research communications 51 12821115
2018 The lncRNA RHPN1-AS1 downregulation promotes gefitinib resistance by targeting miR-299-3p/TNFSF12 pathway in NSCLC. Cell cycle (Georgetown, Tex.) 50 30010468
2021 Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis. The Journal of allergy and clinical immunology 49 33705829
2008 Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke. Journal of the neurological sciences 49 18793781
2014 AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis. Cancer research 48 24970477
2007 Role of TWEAK and Fn14 in tumor biology. Frontiers in bioscience : a journal and virtual library 48 17127278
2012 The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment. The Journal of investigative dermatology 47 23190886
2013 TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation. The Journal of pathology 46 24037740
2000 Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3). FEBS letters 46 11094155
2014 Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis. Frontiers in immunology 43 24550918
2008 Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA. Rheumatology (Oxford, England) 43 18310134
2010 TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer letters 41 20189297
2013 TWEAK: A New Player in Obesity and Diabetes. Frontiers in immunology 39 24416031
2008 TWEAK is expressed at the cell surface of monocytes during multiple sclerosis. Journal of leukocyte biology 38 18945822
2005 Functional expression of TWEAK in human colonic adenocarcinoma cells. International journal of oncology 38 15586228
2014 TWEAK-Fn14 pathway activation after exercise in human skeletal muscle: insights from two exercise modes and a time course investigation. Journal of applied physiology (Bethesda, Md. : 1985) 37 25539934
2014 Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. Molecular cancer research : MCR 36 24469836
2014 Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice. Journal of cellular and molecular medicine 36 24479820
2004 Involvement of GSK-3beta in TWEAK-mediated NF-kappaB activation. FEBS letters 36 15147869
2018 Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis. Experimental and therapeutic medicine 34 29456665
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 34 29981796
2021 TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 33 34155062
2014 TWEAK-Fn14 Cytokine-Receptor Axis: A New Player of Myocardial Remodeling and Cardiac Failure. Frontiers in immunology 33 24611063
2016 Role of the TWEAK/Fn14 pathway in autoimmune diseases. Immunologic research 32 26659091
2014 TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human molecular genetics 32 25504044
2016 TWEAK protects cardiomyocyte against apoptosis in a PI3K/AKT pathway dependent manner. American journal of translational research 31 27725864
2020 TWEAK/Fn14 axis in respiratory diseases. Clinica chimica acta; international journal of clinical chemistry 30 32526219
2019 A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. EBioMedicine 30 31395500
2016 Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury. Seminars in nephrology 30 27339384
2013 BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 proteins are related to human glioma tumor grade: immunohistochemistry and public microarray data meta-analysis. PloS one 30 24376672
2013 Increased expression of atrogenes and TWEAK family members after severe burn injury in nonburned human skeletal muscle. Journal of burn care & research : official publication of the American Burn Association 29 23816995
2009 Therapeutic targeting of TWEAK/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway. Results and problems in cell differentiation 29 19513634
2007 How to tweak a beak: molecular techniques for studying the evolution of size and shape in Darwin's finches and other birds. BioEssays : news and reviews in molecular, cellular and developmental biology 29 17187350
2013 TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation. International journal of oncology 28 24337061
2003 TWE-PRIL; a fusion protein of TWEAK and APRIL. Biochemical pharmacology 28 14555217
2015 Serum levels of TWEAK in patients with psoriasis vulgaris. Cytokine 27 26499979
2020 Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration. Cellular and molecular life sciences : CMLS 26 32200423
2018 TWEAK/Fn14 interaction induces proliferation and migration in human airway smooth muscle cells via activating the NF-κB pathway. Journal of cellular biochemistry 26 29143982
2021 TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome. The Journal of pathology 24 33512736
2019 TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets? Clinical science (London, England : 1979) 24 31097613
2018 TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway. Journal of cellular and molecular medicine 24 29971943
2019 VPS29, a tweak tool of endosomal recycling. Current opinion in cell biology 23 31051431
2014 Nrf2 protects against TWEAK-mediated skeletal muscle wasting. Scientific reports 23 24406502
2012 A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway. Journal of signal transduction 23 22649723
2010 Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer. Experimental and therapeutic medicine 23 22977477
2007 Tweak and FN14 in central nervous system health and disease. Frontiers in bioscience : a journal and virtual library 23 17485258
2023 TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia. Hepatology (Baltimore, Md.) 21 36626628
2021 Bacterial effectors mimicking ubiquitin-proteasome pathway tweak plant immunity. Microbiological research 21 34246833
2016 Tweak up-regulates endothelin-1 system in mouse and human endothelial cells. Cardiovascular research 21 28025386
2018 The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20 29266762
2018 TWEAK/Fn14 Interaction Confers Aggressive Properties to Cutaneous Squamous Cell Carcinoma. The Journal of investigative dermatology 20 30414907