A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44.

Lee, T H; Wisniewski, Hans‐Georg; Vilček, Ján

doi:10.1083/jcb.116.2.545

Cited by 282 publications

(251 citation statements)

References 67 publications

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“…In vivo expression of TSG-6/Tnfip6 has been associated with inflammatory arthritis (3,5), but the protein is produced in a variety of cells exposed to proinflammatory stimuli in vitro (2,28,29), and also in a physiologic process such as matrix formation around the cumulus cell-oocyte complex (30). In fact, the relationship between impaired cumulus cell-oocyte matrix assembly and female sterility in Tnfip6-knockout mice reveals an essential role for this protein in the formation of crosslinked HA fibers around the oocyte that is necessary for the expansion of cumulus matrix and subsequent oocyte fertilization (15).…”

Section: Discussionmentioning

confidence: 99%

“…Tumor necrosis factor ␣ (TNF␣)-induced protein 6 (Tnfip6), the secreted product of TNF␣-stimulated gene 6 (TSG-6), is a member of the hyaladherin superfamily of hyaluronan (HA) binding proteins (1,2). The constitutive expression of Tnfip6 is very low, but virtually all cell types of mesenchyme origin can produce Tnfip6 in response to proinflammatory stimuli (2)(3)(4)(5).…”

mentioning

confidence: 99%

“…The constitutive expression of Tnfip6 is very low, but virtually all cell types of mesenchyme origin can produce Tnfip6 in response to proinflammatory stimuli (2)(3)(4)(5). Tnfip6 can be detected in large quantities in synovial fluid samples from inflamed joints, but not in normal healthy joints (3).…”

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confidence: 99%

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Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Szántó¹,

Bárdos²,

Gál³

et al. 2004

Arthritis & Rheumatism

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Objective. To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor ␣ (TNF␣)-induced protein 6 (Tnfip6) in arthritis, using Tnfip6-deficient animals.Methods. TNF␣-stimulated gene 6 (TSG-6) coding for Tnfip6 was disrupted. Tnfip6-deficient mice were backcrossed into proteoglycan-induced arthritis (PGIA)-susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate-induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild-type and Tnfip6-deficient mice in the presence or absence of treatment with recombinant murine Tnfip6.Results. The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6-deficient mice compared with wild-type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6-deficient mice. This was accompanied by elevated serum levels of interleukin-6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6-null mice, when compared with that of the wild-type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6-null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate-induced peritonitis was 2-fold higher in Tnfip6-deficient animals than in wild-type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6.Conclusion. Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronanrich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6-mediated blocking mechanism.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Szántó¹,

Bárdos²,

Gál³

et al. 2004

Arthritis & Rheumatism

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“…The CUB_C domain of human TSG-6 (residues 129-277 in the preprotein (Lee et al, 1992) with a glutamine at residue 144) was expressed in E. coli. Initial attempts to express the CUB module alone (i.e.…”

Section: Expression and Purification Of Tsg-6 Cub_c Domainmentioning

confidence: 99%

TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly

et al. 2008

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Human plasma fibronectin binds with high affinity to the inflammation-induced secreted protein TSG-6. Fibronectin binds to the CUB_C domain of TSG-6 but not to its Link module. TSG-6 can thus act as a bridging molecule to facilitate fibronectin association with the TSG-6 Link module ligand thrombospondin-1. Fibronectin binding to TSG-6 is divalent cation-independent and is conserved in cellular fibronectins. Based on competition binding studies using recombinant and proteolytic fragments of fibronectin, TSG-6 binding localizes to type III repeats 9-14 of fibronectin. This region of fibronectin contains the Arg-Gly-Asp sequence recognized by α5β1 integrin, but deletion of that sequence does not prevent TSG-6 binding, and TSG-6 does not inhibit cell adhesion on fibronectin substrates mediated by this integrin. This region of fibronectin is also involved in fibronectin matrix assembly, and addition of TSG-6 enhances exogenous and endogenous fibronectin matrix assembly by human fibroblasts. Therefore, TSG-6 is a high affinity ligand that can mediate fibronectin interactions with other matrix components and modulate some interactions of fibronectin with cells.

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“…Indeed, TSG-6 has been shown to associate with many matrix components. For instance, it interacts with the glycosaminoglycans, hyaluronan (HA) [3,13,14] and chondroitin-4-sulphate [25], as well as the hyaluronan-binding region of aggrecan [26], the most common proteoglycan found in disc. In addition, TSG-6 is up-regulated in the matrix surrounding osteoarthritis-like lesions in STR/ort mice, with decreased levels of aggrecan being seen in areas strongly expressing this protein [23].…”

Section: Introductionmentioning

confidence: 99%

TNF?-stimulated gene product (TSG-6) and its binding protein, I?I, in the human intervertebral disc: new molecules for the disc

et al. 2004

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A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44.

Cited by 282 publications

References 67 publications

Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

TSG-6 binds via its CUB_C domain to the cell-binding domain of fibronectin and increases fibronectin matrix assembly

TNF?-stimulated gene product (TSG-6) and its binding protein, I?I, in the human intervertebral disc: new molecules for the disc

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