Affinage

TNFAIP6

Tumor necrosis factor-inducible gene 6 protein · UniProt P98066

Length
277 aa
Mass
31.2 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFAIP6 (TSG-6) is a TNF-α/IL-1-inducible secreted glycoprotein that functions as a broad-spectrum anti-inflammatory mediator and extracellular matrix organizer, acting through its Link and CUB modules to bind hyaluronan, multiple glycosaminoglycans, and chemokines, and to catalyze covalent heavy chain transfer onto hyaluronan. The Link module binds hyaluronan with pH-dependent affinity (maximal at pH 6.0, mediated by His4-controlled conformational switching), and also directly binds CC/CXC chemokines (CXCL8, CCL2, CCL5, and others at nanomolar affinity) at their GAG-binding sites, blocking chemokine presentation on endothelial surfaces and suppressing neutrophil extravasation (PMID:17307731, PMID:27044744, PMID:15457471). The CUB module contains a Ca²⁺-binding site essential for metal ion-dependent transesterification that transfers inter-α-inhibitor heavy chains first onto TSG-6 then onto HA—a catalytic cycle requiring HC2 as obligate cofactor—to form covalent HC·HA matrices critical for cumulus-oocyte complex expansion and tissue remodeling (PMID:15840581, PMID:26468290, PMID:18448433). TSG-6 additionally signals through CD44 on macrophages and microglia to suppress TLR4/NF-κB and STAT pathways, directly binds RANKL and BMP-2 to inhibit osteoclastogenesis and osteoblastogenesis, and constitutes a principal effector of MSC-mediated immunomodulation through an IDO→kynurenic acid→AhR→TSG-6 promoter axis (PMID:27911817, PMID:18586671, PMID:19570514, PMID:29238069).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Establishing that TSG-6 is a primary-response gene transcriptionally activated by TNF-α and IL-1 answered the foundational question of how TSG-6 is induced during inflammation, identifying NF-IL6 and AP-1 promoter elements as the regulatory mechanism.

    Evidence Nuclear run-on, promoter deletion/reporter assays in human fibroblasts

    PMID:7876106 PMID:8454591

    Open questions at the time
    • Full enhancer architecture not mapped
    • Post-transcriptional regulation largely unexplored at this stage
  2. 1997 High

    Demonstrating that TSG-6 forms a stable covalent complex with inter-α-inhibitor (IαI) and that its Link module binds hyaluronan and chondroitin-4-sulfate established TSG-6 as a bifunctional molecule bridging serine protease inhibition and extracellular matrix glycosaminoglycan binding.

    Evidence Biochemical complex isolation, microtiter plate binding assays with competition experiments

    PMID:9237673 PMID:9244409

    Open questions at the time
    • Catalytic mechanism of HC transfer unknown
    • Structural basis of HA recognition unresolved
  3. 2000 High

    NMR mapping of the HA-binding groove on the Link module and ITC-measured affinities resolved which residues mediate HA recognition, revealing a mechanism based on CH-π stacking with sugar rings and ionic contacts with glucuronic acids.

    Evidence NMR chemical shift perturbation and isothermal titration calorimetry with HA oligomers

    PMID:10903951 PMID:15718240

    Open questions at the time
    • pH dependence mechanism not yet molecularly defined
    • Role of CUB module in HA binding unknown
  4. 2002 High

    Showing that the Link module alone inhibits neutrophil migration in vivo independently of HA binding or IαI potentiation revealed a distinct anti-inflammatory mechanism separable from matrix-organizing functions.

    Evidence Site-directed mutagenesis of Link module, murine air pouch model, chimeric CD44/TSG-6 flow assays

    PMID:12011075 PMID:12401803 PMID:15513871

    Open questions at the time
    • Direct molecular target on neutrophils not identified
    • Chemokine-binding mechanism not yet discovered
  5. 2004 High

    TSG-6 knockout mice with enhanced neutrophil infiltration and more severe arthritis provided genetic proof that endogenous TSG-6 is a non-redundant anti-inflammatory factor in vivo.

    Evidence TSG-6 KO mouse with proteoglycan-induced arthritis and thioglycollate peritonitis models

    PMID:15457471

    Open questions at the time
    • Mechanism of neutrophil extravasation inhibition not fully defined
    • Contribution of different TSG-6 activities (HA cross-linking vs. protease inhibition) not dissected in vivo
  6. 2005 High

    Reconstitution of the two-step transesterification reaction—HC transfer from IαI chondroitin sulfate onto TSG-6, then from TSG-6 onto HA—established TSG-6 as a catalytic transferase recycled after HC·HA formation, resolving the enzymatic mechanism of covalent matrix assembly.

    Evidence In vitro reconstitution with purified IαI and recombinant TSG-6, metal ion manipulation, SDS-PAGE

    PMID:15840581 PMID:16768462

    Open questions at the time
    • Active-site residues not identified
    • Structural basis of metal ion requirement unclear
  7. 2007 High

    Identification of His4 as the pH sensor controlling HA affinity—its deprotonation above pH 6.0 disrupts a buried salt bridge network propagating to HA-binding residue Tyr12—provided a molecular explanation for how TSG-6 activity is tuned by inflammatory acidosis.

    Evidence Site-directed mutagenesis, NMR pKa determination, ITC

    PMID:17307731

    Open questions at the time
    • In vivo relevance of pH switching not directly tested
    • Allostery between heparin and HA sites only partially characterized
  8. 2007 High

    Crystal structure and NMR dynamics of the Link module revealed that HA-binding loops are mobile in the free state and rigidified upon HA binding, and that HA binding allosterically dampens mobility at the heparin-binding site, providing structural evidence for functional crosstalk between binding surfaces.

    Evidence X-ray crystallography and ¹⁵N NMR relaxation

    PMID:17585936

    Open questions at the time
    • Full-length TSG-6 structure not determined
    • Structural basis of CUB-Link interplay unknown
  9. 2008 High

    Discovery that HC2 is an obligate cofactor for HC transfer from bikunin-family proteins onto HA defined a specificity checkpoint in the transesterification pathway, and demonstration that TSG-6 inhibits both RANKL-mediated osteoclastogenesis and BMP-2-mediated osteoblastogenesis expanded TSG-6's functional scope to bone remodeling.

    Evidence In vitro reconstitution with purified HC components; osteoclast/osteoblast differentiation assays and TSG-6 KO mouse bone phenotype

    PMID:18448433 PMID:18586671

    Open questions at the time
    • Structural basis of RANKL/BMP-2 binding not resolved
    • HC2 cofactor mechanism at molecular level unknown
  10. 2009 High

    Showing that TSG-6 knockdown in MSCs abolishes cardiac repair after myocardial infarction—and that recombinant TSG-6 alone replicates the effect—identified TSG-6 as a principal paracrine effector of MSC immunotherapy.

    Evidence TSG-6 siRNA in hMSCs, recombinant TSG-6 rescue, mouse MI model

    PMID:19570514

    Open questions at the time
    • Downstream signaling mechanism in cardiac tissue not defined
    • Relative contribution of different TSG-6 activities in cardiac protection unknown
  11. 2011 High

    TSG-6 was shown to signal through CD44 on macrophages to suppress NF-κB nuclear translocation, and full-length TSG-6 was found to oligomerize on HA and cross-link HA matrices—establishing two mechanistically distinct functions: receptor-mediated signaling and physical matrix organization.

    Evidence Zymosan peritonitis model with CD44 interaction studies; QCM-D/AFM on end-grafted HA films

    PMID:21551236 PMID:21596748

    Open questions at the time
    • Oligomerization interface on TSG-6 not structurally defined
    • Whether CD44 signaling requires HA cross-linking not determined
  12. 2014 High

    Quantitative demonstration that TSG-6 directly binds CXCL8 and a panel of CC/CXC chemokines at nanomolar affinity via their GAG-binding sites resolved the long-standing question of how TSG-6 inhibits neutrophil extravasation: by sequestering chemokines and blocking their endothelial presentation.

    Evidence SPR binding measurements, neutrophil transendothelial migration assays, chemokine-GAG competition

    PMID:24501198 PMID:27044744

    Open questions at the time
    • Relative in vivo contribution of chemokine sequestration versus other anti-inflammatory mechanisms not quantified
    • Selectivity determinants for different chemokines not structurally resolved
  13. 2015 High

    Crystal structure of the CUB module revealed the Ca²⁺-binding site mediating HC·TSG-6 intermediate formation and showed that HC transfer onto HA (but not HA binding) is the essential TSG-6 function for cumulus-oocyte complex expansion.

    Evidence CUB module crystal structure, transferase-impaired and HA-binding-impaired mutants in COC expansion assay

    PMID:26468290

    Open questions at the time
    • No full-length TSG-6 structure
    • Atomic details of HC–CUB interaction unknown
  14. 2016 High

    TSG-6 was found to disrupt TLR4-MyD88 association and suppress STAT1/STAT3 signaling in macrophages, and TSG-6 KO mice showed markedly augmented LPS-induced lung injury, defining a TLR4-level signaling checkpoint and confirming an autocrine negative feedback loop.

    Evidence TSG-6 KO mouse LPS lung injury model, co-immunoprecipitation of TLR4-MyD88

    PMID:27911817

    Open questions at the time
    • Direct binding site on TLR4 or MyD88 not identified
    • Whether TSG-6 acts on TLR4 directly or via CD44/HA intermediates not fully resolved
  15. 2017 High

    ChIP demonstrated that AhR directly binds the TSG-6 promoter downstream of IDO-generated kynurenic acid, establishing a transcriptional axis (IDO→KYNA→AhR→TSG-6) that explains how MSC immunosuppression is metabolically regulated.

    Evidence ChIP for AhR on TSG-6 promoter, IDO deletion/inhibition in MSCs, mouse ALI model

    PMID:29238069

    Open questions at the time
    • Whether AhR element cooperates with NF-IL6/AP-1 elements not tested
    • Relevance of this axis outside MSC biology not established
  16. 2022 Medium

    Matrix stiffness was shown to regulate TSG-6 expression through MAPK/Hippo/AP1 signaling, and TSG-6 in colorectal cancer was found to stabilize CD44, promote CD44-EGFR complex formation, and activate ERK/STAT3 signaling—revealing that TSG-6's CD44-dependent functions can be co-opted in cancer.

    Evidence Hydrogel stiffness variation with pathway inhibitors; CRC cell TSG-6 overexpression/knockdown with co-IP and xenograft

    PMID:35280699 PMID:35820593

    Open questions at the time
    • Cancer-associated TSG-6 functions from single studies, not independently replicated
    • Whether TSG-6-CD44-EGFR complex reflects a general mechanism or is cancer-specific is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • No full-length TSG-6 structure exists; the atomic basis of Link-CUB module cooperation during HC transesterification, the structural determinants of TSG-6 oligomerization on HA, and the precise mechanism by which TSG-6 disrupts TLR4-MyD88 signaling remain open questions.
  • Full-length structure needed to understand inter-module allostery
  • TSG-6 oligomerization interface not defined
  • Direct versus CD44/HA-mediated action on TLR4 signaling not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 6 GO:0098772 molecular function regulator activity 5 GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 3
Pathway
R-HSA-168256 Immune System 6 R-HSA-1474244 Extracellular matrix organization 5 R-HSA-162582 Signal Transduction 5 R-HSA-1474165 Reproduction 2
Partners
BMP2CD44CXCL8ITIH1ITIH2THBS1TLR4TNFSF11
Complex memberships
HC·HA complexIαI·TSG-6 (HC·TSG-6 covalent intermediate)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 TSG-6 gene is transcriptionally activated by TNF-α and IL-1 as a primary response gene in human fibroblasts; the TSG-6 gene was mapped to human chromosome 2 and its promoter region contains NF-IL6, AP-1, and IRF binding sites that mediate cytokine-induced transcription. Deletion analysis showed a region from -165 to -58 bp confers IL-1/TNF inducibility. Nuclear run-on transcription assay, Southern blot, primer extension, deletion analysis with CAT reporter gene transfection The Journal of biological chemistry High 8454591
1995 Activation of the TSG-6 promoter by NF-IL6 requires two functionally interdependent adjacent NF-IL6 binding sites (at positions -106 to -114 and -92 to -83); mutation of either site greatly decreased or abolished NF-IL6-driven transcription. Footprinting, EMSA, site-directed mutagenesis, reporter gene (CAT) transfection The Journal of biological chemistry High 7876106
1997 TSG-6 forms a stable covalent complex (~120 kDa) with the serum protease inhibitor inter-alpha-inhibitor (IαI) and potentiates IαI's anti-plasmin activity, constituting a mechanism for TSG-6's anti-inflammatory effects via modulation of the protease network. Biochemical complex isolation, anti-plasmin activity assay, SDS-PAGE Cytokine & growth factor reviews Medium 9244409
1997 The Link module of TSG-6 binds hyaluronan and chondroitin-4-sulphate at overlapping sites, but does not bind chondroitin-6-sulphate or heparin; this was determined by microtiter plate-based binding assays and competition experiments. Microtiter plate binding assay with biotinylated hyaluronan and biotinylated Link module, competition experiments FEBS letters High 9237673
1998 TSG-6 binds hyaluronan and aggrecan through a common binding surface in a pH-dependent manner, with maximal binding at pH 6.0 and dramatic loss of function at higher pH, suggesting TSG-6 activity is regulated by pH gradients in inflamed cartilage. Microtiter plate binding assays at different pH values, competition experiments with hyaluronan FEBS letters High 9654129
2000 The HA-binding site on the Link module of TSG-6 was localized by NMR spectroscopy to residues Lys11, Tyr59, Asn67, Phe70, Lys72, and Tyr78, and isothermal titration calorimetry showed that a single Link module is sufficient for high-affinity HA binding (KD ~0.2–0.5 μM for HA oligomers ≥6-mers). NMR spectroscopy (chemical shift perturbation), isothermal titration calorimetry Structure High 10903951
2001 TSG-6 co-localizes with IαI and hyaluronan in the cumulus-oocyte complex extracellular matrix, and Western blot confirmed the presence of both free TSG-6 and TSG-6/IαI complexes in ovulated COCs, suggesting TSG-6 has a structural role in COC matrix formation possibly by cross-linking HA molecules via IαI. Immunofluorescence, laser confocal microscopy, Western blot Biology of reproduction Medium 11420253
2002 The isolated recombinant Link module of TSG-6 (Link_TSG6) inhibits neutrophil migration in vivo equivalently to full-length protein in an HA-binding and IαI-complex-independent manner; mutagenesis of six residues showed this anti-inflammatory activity is entirely within the Link module but is not dependent on HA binding or potentiation of IαI anti-plasmin activity. In vivo murine air pouch model, in vitro anti-plasmin assay, site-directed mutagenesis of Link module, recombinant protein production in Drosophila expression system The Journal of biological chemistry High 12401803
2002 Replacement of the CD44 Link module with the TSG-6 Link module (higher HA affinity) converted rolling leukocyte behavior to firm tethering under flow, demonstrating that the low intrinsic HA affinity of CD44's Link module (relative to TSG-6's) is mechanistically important for leukocyte rolling. CD44/TSG-6 chimera expression in cells, parallel plate flow assay, hyaluronan binding assays The Journal of biological chemistry High 12011075
2004 TSG-6 preincubation with hyaluronan enhances or induces CD44-mediated HA binding on lymphoid cells; this is mediated through the Link module's HA-binding function and may involve TSG-6-mediated HA cross-linking that promotes receptor clustering and increases binding avidity. Cell binding assays, CD44-blocking antibodies, CD44-negative cell controls, flow assays The Journal of biological chemistry High 15060082
2004 TSG-6-knockout mice show enhanced neutrophil extravasation, elevated plasmin/myeloperoxidase/neutrophil elastase activities in inflamed joints, and more severe proteoglycan-induced arthritis, demonstrating that endogenous TSG-6 inhibits neutrophil extravasation and protease activity at inflammatory sites. TSG-6 knockout mouse, proteoglycan-induced arthritis model, thioglycollate peritonitis model, enzyme activity assays Arthritis and rheumatism High 15457471
2004 The TSG-6 Link module inhibits leukocyte rolling, adhesion, and emigration in IL-1β–inflamed mesenteries in vivo, and inhibits neutrophil transmigration across endothelial monolayers in vitro, without affecting neutrophil chemotaxis or endothelial cell activation directly. Intravital microscopy of mouse mesentery, in vitro neutrophil transmigration assay Microcirculation High 15513871
2005 TSG-6 acts as a cofactor and catalyst (transferase) for the formation of heavy chain-HA (HC·HA) complexes: it forms covalent HC·TSG-6 intermediates (TSG-6·HC1 and TSG-6·HC2) via transesterification from IαI chondroitin sulfate, then transfers HCs onto HA in a second metal ion-dependent (Mg2+ or Mn2+; inhibited by Co2+) transesterification; TSG-6 is then recycled. In vitro reconstitution with purified IαI and recombinant TSG-6, SDS-PAGE, metal ion substitution/chelation experiments The Journal of biological chemistry High 15840581
2005 The N-terminal module of thrombospondin-1 (TSP1) binds directly to the Link module of TSG-6 (KD comparable to TSG-6's GAG interactions); heparin (bound to TSP1) inhibits the interaction. TSP1 enhances covalent HC·TSG-6 formation and subsequent HC transfer onto HA. Radioligand binding assay (125I-TSP1), recombinant domain mapping, heparin/hyaluronan competition, in vitro HC transfer assay The Journal of biological chemistry High 16006654
2005 Full-length TSG-6 binds hyaluronan to form a stable, dissociation-resistant complex in a temperature-dependent manner; TSG-6 also binds all chondroitin sulfate isoforms under physiological conditions. TSG-6 binding to immobilized HA does not block subsequent lymphoid cell adhesion to HA. Protein-HA binding assay with dissociating agents, temperature dependence, cell adhesion assay The Journal of biological chemistry High 15699048
2005 NMR spectroscopy combined with molecular modeling defined the HA-binding groove of the TSG-6 Link module in detail: two adjacent tyrosine residues form CH-π stacking interactions with HA sugar rings, acetamido groups of GlcNAc fit into hydrophobic pockets providing HA selectivity over other polysaccharides, and two basic residues form salt bridges with glucuronic acids. NMR spectroscopy with 13C/15N-labeled HA, molecular docking, sequence alignment/homology modeling The Journal of biological chemistry High 15718240
2006 Two-step mechanism for HC·TSG-6 complex formation: (1) a cation-independent non-covalent interaction between TSG-6 and the chondroitin sulfate chain of IαI (KD ~180 nM at site 1); (2) a cation-dependent (Mn2+, Mg2+, or Ca2+) transesterification generating the covalent HC·TSG-6 cross-link at a distinct site 2; intact native folds of both IαI and TSG-6 and an intact chondroitin sulfate chain are required. In vitro reconstitution with purified proteins, divalent cation manipulation, limited proteolysis, chondroitin sulfate cleavage Biochemistry High 16768462
2006 Heparin binding to TSG-6's Link module inhibits subsequent HA binding even though heparin binds a distinct site from HA, revealing allosteric communication between the heparin-binding and HA-binding sites; pH also modulates binding to HA, heparin, and protein ligands, suggesting differential partitioning of TSG-6 function in different tissue microenvironments. Binding competition assays, pH variation studies, glycosaminoglycan specificity profiling Biochemical Society transactions Medium 16709183
2007 The pH-dependent interaction of TSG-6 with HA is mechanistically mediated by His4: upon deprotonation above pH 6.0, His4 disrupts a salt bridge with buried Asp89, which is simultaneously hydrogen-bonded to key HA-binding residue Tyr12, thereby reducing HA affinity. His45 is responsible for affinity gain between pH 3.5 and 6.0. Site-directed mutagenesis, NMR (pKa determination, folding profiles), isothermal titration calorimetry, microtiter plate assays The Journal of biological chemistry High 17307731
2007 X-ray crystallography and 15N NMR relaxation of the TSG-6 Link module revealed high mobility in the β4/β5 loop and at the Cys47-Cys68 disulfide bond (both HA-binding regions) in the free protein; HA binding dampens this mobility. Lys54 (heparin-binding site) becomes less mobile when HA is bound, providing evidence for allostery between the HA and heparin-binding sites. X-ray crystallography, 15N NMR relaxation, heparin docking calculations Journal of molecular biology High 17585936
2008 TSG-6 inhibits RANKL-induced osteoclast differentiation/activation and BMP-2-mediated osteoblast differentiation via direct binding to RANKL and BMP-2 (but not BMP-3) through composite surfaces involving both its Link and CUB modules; TSG-6-knockout mice have elevated trabecular bone mass in unchallenged conditions. In vitro osteoclast and osteoblast differentiation assays, direct protein-protein binding (interaction analysis), TSG-6 KO mouse bone phenotype The Journal of biological chemistry High 18586671
2008 Confocal FRAP demonstrated that the TSG-6 Link module binds polymeric HA with maximal affinity at pH 6.0 (100-fold higher affinity than at pH 7.4), while aggrecan G1 has maximal binding at pH 7.0–8.0, explaining their differential roles in normal versus inflamed cartilage. Confocal fluorescence recovery after photobleaching (FRAP) with labeled proteins The Journal of biological chemistry High 18806261
2008 HC transfer from bikunin proteins to HA requires both TSG-6 and HC2: HC2 (from IαI, HC2.bikunin, or free HC2) promotes formation of HC3·TSG-6 and subsequently HC3·HA complexes; HC1 or HC3 alone cannot perform this role. In vitro reconstitution with purified components from human plasma, SDS-PAGE identification The Journal of biological chemistry High 18448433
2009 Intravenously infused human MSCs become trapped as emboli in the lung and are activated to upregulate TSG-6 expression; TSG-6 knockdown (siRNA) in hMSCs abolishes the reduction of infarct size and inflammatory responses after myocardial infarction, and recombinant TSG-6 alone replicates the therapeutic effect. Quantitative human DNA/mRNA tracking in tissues, TSG-6 siRNA knockdown in hMSCs, recombinant TSG-6 administration, mouse myocardial infarction model Cell stem cell High 19570514
2011 TSG-6 interacts with CD44 on resident peritoneal macrophages to decrease zymosan/TLR2-mediated nuclear translocation of NF-κB, establishing a CD44-dependent mechanism by which TSG-6 reduces macrophage-driven inflammation. Zymosan-induced peritonitis model, NF-κB nuclear translocation assay, CD44 interaction studies Blood High 21551236
2011 Full-length TSG-6 cross-links HA via HA-induced TSG-6 oligomerization (positive cooperative binding); the TSG-6 oligomers act as cross-linkers that condense and rigidify HA films. The isolated Link module alone binds HA without cooperativity and with lower affinity and cannot cross-link HA. End-grafted HA films, quartz crystal microbalance, surface-sensitive biophysical techniques (QCM-D, reflectometry), atomic force microscopy The Journal of biological chemistry High 21596748
2011 TSG-6 inhibits RANKL-mediated osteoclast activation via an autocrine mechanism: osteoclast precursors and mature osteoclasts produce TSG-6 in response to TNFα, IL-1, and IL-6, and anti-TSG-6 antibody increases lacunar resorption. TSG-6 acts synergistically with osteoprotegerin. Osteoclast differentiation/resorption assays, anti-TSG-6 neutralizing antibody, ELISA for TSG-6 in conditioned media and synovial fluid Arthritis and rheumatism High 21162099
2012 TSG-6 amplifies hyaluronan synthesis by airway smooth muscle cells: when added together with poly(I:C), TSG-6 increases HA accumulation in the cell-associated matrix and induces HA synthesis, an effect absent with TSG-6 alone. This occurs via a mechanism independent of TSG-6, HAS1/3, or CD44 on the smooth muscle cells themselves. Airway smooth muscle cell cultures from TSG-6−/−, HAS1/3−/−, and CD44−/− mice, HA accumulation assays, poly(I:C) stimulation The Journal of biological chemistry High 23129777
2013 IαI impairs TSG-6-induced HA cross-linking: in the presence of IαI, TSG-6-mediated cross-linking and condensation of HA films is suppressed, and this suppresses TSG-6-mediated enhancement of HA binding to CD44-positive cells. Two types of TSG-6/IαI complexes form on HA: covalent HC·TSG-6 (weakly bound to HA) and a novel noncovalent HA-stable complex. End-grafted HA films, surface-sensitive biophysics (QCM-D, reflectometry), CD44-positive cell binding assays The Journal of biological chemistry High 24005673
2013 Assembly of MSCs into spheres activates caspase-dependent IL-1α/β signaling, which drives upregulation of TSG-6, STC1, and COX2/PGE2. Inhibitors of caspases reduce IL-1A/B expression; inhibitors of IL-1 signaling decrease TSG-6 and PGE2 production and negate anti-inflammatory effects on macrophages. Hanging drop sphere cultures, caspase inhibitors, IL-1 signaling inhibitors, Notch inhibitors (γ-secretase), gene expression profiling Stem cells High 23922312
2014 TSG-6 directly binds CXCL8 (KD ~25 nM) at the CXCL8 glycosaminoglycan-binding site via the TSG-6 Link module, antagonizing CXCL8-heparin association, impairing CXCL8 binding to cell-surface glycosaminoglycans, blocking CXCL8 transcytosis across endothelial monolayers, and suppressing CXCL8-stimulated neutrophil transendothelial migration. SPR/binding affinity measurement, neutrophil transendothelial migration assay, CXCL8-heparin competition assay, CXCL8 cell-surface binding assay, transcytosis assay Journal of immunology High 24501198
2014 TSG-6 refined NMR-based model of the Link module-HA complex: HA makes more extensive contacts than previously thought; a glucuronic acid ring makes stacking and ionic interactions with a histidine and lysine, causing HA to bend around two faces of the Link module in a manner resembling CD44-HA interaction. The HA-binding site is NOT used for recognition during HC transfer onto HA. NMR spectroscopy with 10 distinct HA oligosaccharides (4- to 8-mers), 13C-labeled octasaccharide, chondroitin/HA hybrid oligomers, TSG-6 mutant analysis The Journal of biological chemistry High 24403066
2014 TSG-6 inhibits LPS-induced NF-κB and MAPK pathway activation in BV2 microglial cells in a CD44-dependent manner; knockdown of CD44 in BV2 cells abrogated TSG-6-mediated inhibition of pro-inflammatory gene expression and NF-κB/MAPK activation. LPS-stimulated BV2 microglial cell culture, TSG-6 treatment, CD44 siRNA knockdown, NF-κB/MAPK pathway analysis by Western blot Journal of neuroinflammation High 25088370
2015 The TSG-6 CUB module structure was determined, revealing a calcium ion-binding site with a chelating glutamic acid residue that mediates formation of HC·TSG-6 intermediates via an initial metal ion-dependent noncovalent interaction between TSG-6 and HCs (also requiring an HC-associated Mg2+). The Link module HA-binding site is not required for HC transfer onto HA; only TSG-6 transferase activity (not HA binding) is essential for COC expansion. Crystal structure determination of CUB module, TSG-6 mutant analysis (transferase-impaired and HA-binding-impaired), in vitro COC expansion assay The Journal of biological chemistry High 26468290
2015 TSG-6 in muscle injury microenvironments is required for MSC engraftment: TSG-6 produced by MSCs in response to injury signals (C2C12 myotube lysate) promotes formation of SHAP-HA complexes (covalent HC·HA) that are required for MSC settlement in skeletal muscle; TSG-6 shRNA knockdown prevents settlement. Mouse MSC transplantation model, TSG-6 shRNA knockdown, immunofluorescence co-localization of HA/IαI/TSG-6, in vitro stimulation with C2C12 lysate The Journal of biological chemistry High 26178374
2016 TSG-6 (via its Link module) binds multiple CC and CXC chemokines (CXCL4, CXCL8, CXCL11, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21, CCL27; KD 1–85 nM) at their GAG-binding sites, and also masks cell-surface GAGs, thereby broadly inhibiting chemokine presentation on endothelial cells and impairing GAG-dependent chemokine function. Surface plasmon resonance (KD measurement), chemokine-GAG competition assays, endothelial cell chemokine presentation assay The Journal of biological chemistry High 27044744
2016 TSG-6 inhibits TLR4-MyD88 association in macrophages, suppresses NF-κB activation, STAT1, and STAT3 activation, converts macrophages from proinflammatory to anti-inflammatory phenotype, and TSG-6-knockout mice show markedly augmented LPS-induced lung injury; LPS itself upregulates TSG-6 expression, suggesting an autocrine negative feedback loop. TSG-6−/− mice (LPS lung injury model), co-immunoprecipitation (TLR4-MyD88 association), macrophage phenotype markers, NF-κB/STAT Western blot Proceedings of the National Academy of Sciences High 27911817
2017 IDO metabolite kynurenic acid (KYNA) produced by MSCs activates the aryl hydrocarbon receptor (AhR), which directly binds to the TSG-6 promoter and enhances TSG-6 expression; thus IDO controls TSG-6-mediated immunosuppression via the IDO→KYNA→AhR→TSG-6 axis. IDO deletion/inhibition in human MSCs, KYNA production inhibition, AhR activation assays, chromatin immunoprecipitation (AhR binding to TSG-6 promoter), mouse ALI model Cell death and differentiation High 29238069
2011 TSG-6 controls epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells: TGFβ1 induces TSG-6 expression and causes HA cable disassembly with formation of dense pericellular HA coats; stable knockdown of TSG-6 increases E-cadherin, prevents α-SMA induction, disrupts HA macromolecular structure, and slows cell migration, demonstrating TSG-6 is required for TGFβ1-mediated EMT via HA reorganization and CD44-dependent signaling. Stable shRNA knockdown, CD44 siRNA, TGFβ1 stimulation, immunolocalization of HA, cell migration assay, Western blot for EMT markers International journal of biochemistry & cell biology High 21864707
2012 TSG-6 knockdown by siRNA in fibroblasts upregulates MMP-1 and MMP-3 transcription and triggers extracellular active MMP-1 expression, demonstrating that TSG-6 normally suppresses MMP-1 transcription and prevents MMP-1 activation; this was further enhanced by IL-1β in TSG-6-deficient cells. TSG-6 siRNA knockdown in human conjunctival fibroblasts, qRT-PCR, Western blot, immunostaining of TSG-6/MMP-1/MMP-3 Investigative ophthalmology & visual science High 22297496
2022 Matrix stiffness mechanosensitively regulates TSG-6 expression in MSCs through MAPK and Hippo signaling pathways and the downstream AP1 transcription factor complex; TSG-6 produced from MSCs on soft matrices then acts on macrophages through CD44 receptor to inhibit NF-κB pathway and promote anti-inflammatory polarization. MSC culture on hydrogels of varying stiffness, MAPK/Hippo pathway inhibitors, AP1 inhibitors, CD44 receptor studies, macrophage polarization assays, subcutaneous implantation in vivo Acta biomaterialia Medium 35820593
2022 TSG-6 in colorectal cancer cells stabilizes CD44 and facilitates CD44-EGFR complex formation on the cell membrane, activating ERK signaling and epithelial-mesenchymal transition to promote migration/invasion; secreted TSG-6 also triggers paracrine JAK2-STAT3 signaling to reprogram normal fibroblasts into cancer-associated fibroblasts that upregulate CCL5 and MMP3. TSG-6 overexpression/knockdown in CRC cells, co-immunoprecipitation (CD44-EGFR complex), ERK/STAT3 Western blot, in vitro migration/invasion assays, co-injection xenograft model International journal of biological sciences Medium 35280699
2021 miR-214-5p was identified as a negative regulator of TSG-6 mRNA in adipose-derived stem cells; TNFα stimulation of ADSCs upregulates TSG-6 (overriding miR-214-5p repression), and ADSC-derived TSG-6 inhibits LPS-induced proinflammatory cytokine production in BV2 microglia. High-throughput RNA sequencing, bioinformatics, microRNA-target identification, TSG-6/cytokine ELISA BioMed research international Low 30584538

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell stem cell 1493 19570514
2011 Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood 538 21551236
2003 TSG-6: a multifunctional protein associated with inflammation. Journal of cell science 313 12692188
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2013 TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds. The Journal of investigative dermatology 195 23921952
2010 Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proceedings of the National Academy of Sciences of the United States of America 190 20837529
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2013 Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1). Stem cells (Dayton, Ohio) 159 23922312
2016 TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proceedings of the National Academy of Sciences of the United States of America 158 27911817
2005 Characterization of complexes formed between TSG-6 and inter-alpha-inhibitor that act as intermediates in the covalent transfer of heavy chains onto hyaluronan. The Journal of biological chemistry 151 15840581
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2018 Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem cell research & therapy 150 29941022
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2021 A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6. Stem cell research & therapy 132 34051868
2013 TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. Diabetes 125 23349496
2011 The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers. The Journal of biological chemistry 116 21596748
2002 The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan- and inter-alpha -inhibitor-independent manner. The Journal of biological chemistry 106 12401803
2014 Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6. Journal of neuroinflammation 99 25088370
2015 The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6. Journal of neuroinflammation 96 25890011
2018 TSG-6 attenuates inflammation-induced brain injury via modulation of microglial polarization in SAH rats through the SOCS3/STAT3 pathway. Journal of neuroinflammation 94 30126439
2012 Mesenchymal stem cells attenuate peritoneal injury through secretion of TSG-6. PloS one 90 22912904
2016 The Anti-inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine/Glycosaminoglycan Interactions. The Journal of biological chemistry 88 27044744
2013 Administration of TSG-6 improves memory after traumatic brain injury in mice. Neurobiology of disease 85 23851308
2001 TSG-6 is concentrated in the extracellular matrix of mouse cumulus oocyte complexes through hyaluronan and inter-alpha-inhibitor binding. Biology of reproduction 84 11420253
2009 Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6. Journal of leukocyte biology 79 19389798
2017 Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner. Molecular therapy : the journal of the American Society of Gene Therapy 78 29301108
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2004 Enhanced neutrophil extravasation and rapid progression of proteoglycan-induced arthritis in TSG-6-knockout mice. Arthritis and rheumatism 76 15457471
2022 Exosomes from LPS-preconditioned bone marrow MSCs accelerated peripheral nerve regeneration via M2 macrophage polarization: Involvement of TSG-6/NF-κB/NLRP3 signaling pathway. Experimental neurology 69 35690131
2020 Exosomes derived from TSG-6 modified mesenchymal stromal cells attenuate scar formation during wound healing. Biochimie 69 32800897
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2002 Hyaluronan binding properties of a CD44 chimera containing the link module of TSG-6. The Journal of biological chemistry 65 12011075
2002 Reduced susceptibility to collagen-induced arthritis in DBA/1J mice expressing the TSG-6 transgene. Arthritis and rheumatism 64 12355494
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2020 Liver-targeted delivery of TSG-6 by calcium phosphate nanoparticles for the management of liver fibrosis. Theranostics 62 31903104
2000 Amelioration of collagen-induced arthritis in DBA/1J mice by recombinant TSG-6, a tumor necrosis factor/interleukin-1-inducible protein. Arthritis and rheumatism 62 11145024
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2013 Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs. American journal of physiology. Lung cellular and molecular physiology 53 24242012
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2015 Metal Ion-dependent Heavy Chain Transfer Activity of TSG-6 Mediates Assembly of the Cumulus-Oocyte Matrix. The Journal of biological chemistry 49 26468290
2021 Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis. Stem cell research & therapy 48 33422134
2008 TSG-6 regulates bone remodeling through inhibition of osteoblastogenesis and osteoclast activation. The Journal of biological chemistry 47 18586671
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2018 TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-κB signaling pathway. Laboratory investigation; a journal of technical methods and pathology 45 29483622
2012 Tumor necrosis factor-stimulated gene-6 (TSG-6) amplifies hyaluronan synthesis by airway smooth muscle cells. The Journal of biological chemistry 44 23129777
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2014 A refined model for the TSG-6 link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function. The Journal of biological chemistry 43 24403066
2008 TIMP-1 expression in human colorectal cancer is associated with TGF-B1, LOXL2, INHBA1, TNF-AIP6 and TIMP-2 transcript profiles. Molecular oncology 42 19383344
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2019 Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer's Disease. Journal of Alzheimer's disease : JAD 41 30507579
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2022 Mesenchymal stem/stromal cells primed by inflammatory cytokines alleviate psoriasis-like inflammation via the TSG-6-neutrophil axis. Cell death & disease 37 36433947
2017 Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6. Scientific reports 37 28963485
2015 Topical TSG-6 Administration Protects the Ocular Surface in Two Mouse Models of Inflammation-Related Dry Eye. Investigative ophthalmology & visual science 37 26244293
2005 TSG-6 protein binding to glycosaminoglycans: formation of stable complexes with hyaluronan and binding to chondroitin sulfates. The Journal of biological chemistry 36 15699048
2021 HGF and TSG-6 Released by Mesenchymal Stem Cells Attenuate Colon Radiation-Induced Fibrosis. International journal of molecular sciences 35 33670243
2005 The N-terminal module of thrombospondin-1 interacts with the link domain of TSG-6 and enhances its covalent association with the heavy chains of inter-alpha-trypsin inhibitor. The Journal of biological chemistry 35 16006654
2024 TSG6-Exo@CS/GP Attenuates Endometrium Fibrosis by Inhibiting Macrophage Activation in a Murine IUA Model. Advanced materials (Deerfield Beach, Fla.) 34 38588501
2021 Placental chorionic plate-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating macrophage polarization via secreting TSG-6. Stem cell research & therapy 34 34112260
2018 Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis. Biomaterials science 34 29564448
2016 Comparison of Topical Application of TSG-6, Cyclosporine, and Prednisolone for Treating Dry Eye. Cornea 34 26807900
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2014 Adipose tissue-derived stem cells suppress acute cellular rejection by TSG-6 and CD44 interaction in rat kidney transplantation. Transplantation 34 24983309
2008 The transfer of heavy chains from bikunin proteins to hyaluronan requires both TSG-6 and HC2. The Journal of biological chemistry 33 18448433
2012 Anti-inflammatory recombinant TSG-6 stabilizes the progression of focal retinal degeneration in a murine model. Journal of neuroinflammation 32 22452753
2021 Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching. American journal of physiology. Renal physiology 30 33554782
2022 TSG-6 promotes Cancer Cell aggressiveness in a CD44-Dependent Manner and Reprograms Normal Fibroblasts to create a Pro-metastatic Microenvironment in Colorectal Cancer. International journal of biological sciences 29 35280699
2022 Matrix stiffness regulates the immunomodulatory effects of mesenchymal stem cells on macrophages via AP1/TSG-6 signaling pathways. Acta biomaterialia 28 35820593
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2021 BMSCs Regulate Astrocytes through TSG-6 to Protect the Blood-Brain Barrier after Subarachnoid Hemorrhage. Mediators of inflammation 26 34305453
2007 Determining the molecular basis for the pH-dependent interaction between the link module of human TSG-6 and hyaluronan. The Journal of biological chemistry 26 17307731
2015 Human adipose-derived stem cells ameliorate cigarette smoke-induced murine myelosuppression via secretion of TSG-6. Stem cells (Dayton, Ohio) 25 25329668
2008 Hyaluronan binding to link module of TSG-6 and to G1 domain of aggrecan is differently regulated by pH. The Journal of biological chemistry 25 18806261
2006 Evidence for a two-step mechanism involved in the formation of covalent HC x TSG-6 complexes. Biochemistry 25 16768462
2022 Mesenchymal stem cells protect against TBI-induced pyroptosis in vivo and in vitro through TSG-6. Cell communication and signaling : CCS 24 35982465
2020 Potential of Extracellular Vesicle-Associated TSG-6 from Adipose Mesenchymal Stromal Cells in Traumatic Brain Injury. International journal of molecular sciences 24 32942629
2015 Analysis of the heavy-chain modification and TSG-6 activity in pathological hyaluronan matrices. Methods in molecular biology (Clifton, N.J.) 24 25325979
2015 Acute and temporal expression of tumor necrosis factor (TNF)-α-stimulated gene 6 product, TSG6, in mesenchymal stem cells creates microenvironments required for their successful transplantation into muscle tissue. The Journal of biological chemistry 22 26178374
2007 Plasticity of the TSG-6 HA-binding loop and mobility in the TSG-6-HA complex revealed by NMR and X-ray crystallography. Journal of molecular biology 22 17585936
2020 Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation. Stem cell research & therapy 21 31931878
2018 Upregulated TSG-6 Expression in ADSCs Inhibits the BV2 Microglia-Mediated Inflammatory Response. BioMed research international 21 30584538
2016 Scalable Production of a Multifunctional Protein (TSG-6) That Aggregates with Itself and the CHO Cells That Synthesize It. PloS one 20 26793973
2016 TNFAIP6 is a potential biomarker of disease activity in inflammatory bowel disease. Biomarkers in medicine 20 27088253
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2021 Hyaluronic acid synthesis, degradation, and crosslinking in equine osteoarthritis: TNF-α-TSG-6-mediated HC-HA formation. Arthritis research & therapy 19 34416923
2020 TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation. Frontiers in pharmacology 19 32116692
2016 Mesenchymal Stem Cells Ameliorated Glucolipotoxicity in HUVECs through TSG-6. International journal of molecular sciences 19 27043548
2022 Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Acute Lung Injury Caused by Severe Burn via Secreting TSG-6 and Inhibiting Inflammatory Response. Stem cells international 18 35222649
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2012 TSG-6 controls transcription and activation of matrix metalloproteinase 1 in conjunctivochalasis. Investigative ophthalmology & visual science 17 22297496
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1995 Activation of the TSG-6 gene by NF-IL6 requires two adjacent NF-IL6 binding sites. The Journal of biological chemistry 17 7876106