TSG-6: An IL-1 /TNF-inducible protein with anti-inflammatory activity

Wisniewski, Hans‐Georg; Vilček, Ján

doi:10.1016/s1359-6101(97)00008-7

Cited by 186 publications

(164 citation statements)

References 103 publications

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“…There is little or no constitutive expression of TSG-6 in adult tissues, but the protein is synthesized by fibroblasts, chondrocytes, monocytes, and vascular endothelial, and smooth muscle cells in response to stimulation with pro-inflammatory mediators or certain growth factors. TSG-6 protein has been detected at high levels in the synovial fluids of patients with arthritis and has been localized in articular cartilage and synovium from individuals with osteoarthritis and rheumatoid arthritis but is absent in normal joint tissues (16,19). Although exogenous TSG-6 has been shown to have anti-inflammatory activity in certain in vivo model systems (20 -24), the function of endogenously produced TSG-6 in the inflammatory milieu is unknown.…”

mentioning

confidence: 99%

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

Lesley

Gál

Mahoney

et al. 2004

Journal of Biological Chemistry

160

203

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Interactions between CD44 and hyaluronan are implicated in the primary adhesion of lymphocytes to endothelium at inflammatory locations. Here we show that preincubation of hyaluronan with full-length recombinant TSG-6 or its Link module domain (Link_TSG6) enhances or induces the binding of hyaluronan to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. These effects are blocked by CD44-specific antibodies and are absent in CD44-negative cells. Enhancement of CD44-mediated interactions of lymphoid cells with hyaluronan by TSG-6 proteins was seen under conditions of flow at shear forces that occur in post-capillary venules. Increases in the number of rolling cells were observed on substrates comprising TSG-6-hyaluronan complexes as compared with a substrate containing hyaluronan alone. In ligand competition experiments, cell surface-bound TSG-6-hyaluronan complexes were more potent than hyaluronan alone in inhibiting cell adhesion to immobilized hyaluronan. Link_TSG6 mutants with impaired hyaluronan binding function had a reduced ability to modulate ligand binding by cell surface CD44. However, some mutants that exhibited close to wild-type hyaluronan binding were found to have either reduced or increased activity, suggesting that some amino acid residues outside of the hyaluronan binding site might be involved in protein self-association, potentially leading to the formation of cross-linked hyaluronan fibers. In turn, cross-linked hyaluronan could increase the binding avidity of CD44 by inducing receptor clustering. The ability of TSG-6 to modulate the interaction of hyaluronan with CD44 has important implications for CD44-mediated cell activity at sites of inflammation, where TSG-6 is expressed.

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mentioning

confidence: 99%

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44

Lesley

Gál

Mahoney

et al. 2004

Journal of Biological Chemistry

160

203

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“…TSG-6 (the secreted ϳ35-kDa product of tumor necrosis factor (TNF)-stimulated gene-6 (7)) may be one such endogenous regulator of PMN migration (8,9). In this regard, it has been found that full-length recombinant human TSG-6 (expressed in insect cells (10)) is a potent inhibitor of neutrophil influx in a mouse air pouch model of acute inflammation (8).…”

mentioning

confidence: 99%

The Link Module from Human TSG-6 Inhibits Neutrophil Migration in a Hyaluronan- and Inter-α-inhibitor-independent Manner

Getting¹,

Mahoney²,

Cao³

et al. 2002

Journal of Biological Chemistry

118

152

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TSG-6 protein (the secreted product of the tumor necrosis factor-stimulated gene-6), a hyaluronan-binding protein comprised mainly of a Link and CUB module arranged in a contiguous fashion, has been shown previously to be a potent inhibitor of neutrophil migration in an in vivo model of acute inflammation (Wisniewski, H. G., Hua, J. C., Poppers, D. M., Naime, D., Vilcek, J., and Cronstein, B. N. (1996) J. Immunol. 156, 1609 -1615). It was hypothesized that this activity of TSG-6 was likely to be mediated by its potentiation of inter-␣-inhibitor anti-plasmin activity (causing a down-regulation of the protease network), which was reliant on these proteins forming a stable, probably covalent ϳ120-kDa complex. Here we have shown that the recombinant Link module from human TSG-6 (Link_TSG6; expressed in Escherichia coli) has an inhibitory effect on neutrophil influx into zymosan A-stimulated murine air pouches, equivalent to that of full-length protein (which we produced in a Drosophila expression system). The active dose of 1 g of Link_TSG6 per mouse (administered intravenously) also resulted in a significant reduction in the concentrations of various inflammatory mediators (i.e. tumor necrosis factor-␣, KC, and prostaglandin E 2 ) in air pouch exudates. Link_TSG6, although unable to form a stable complex with inter-␣-inhibitor (under conditions that promote maximum complex formation with the fulllength protein), could potentiate its anti-plasmin activity. This demonstrates that formation of an ϳ120-kDa TSG-6⅐inter-␣-inhibitor complex is not required for TSG-6 to enhance the serine protease inhibitory activity of inter-␣-inhibitor. Six single-site Link_TSG6 mutants (with wild-type folds) were compared for their abilities to inhibit neutrophil migration in vivo, bind hyaluronan, and potentiate inter-␣-inhibitor. These experiments indicate that all of the inhibitory activity of TSG-6 resides within the Link module domain, and that this anti-inflammatory property is not related to either its hyaluronan binding function or its potentiation of the anti-plasmin activity of inter-␣-inhibitor.

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“…TSG-6 could initiate a negative-feedback mechanism to ''switch off'' or interrupt the inflammatory cascade, by inhibiting destructive enzymes by binding to IaI [7,33]. Although IaI is a relatively weak serine protease inhibitor in its own right and its inhibition of plasmin, at least, is significantly increased by binding to TSG-6 [7,32].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, antibodies to TNFa are being used in clinical trials with encouraging results [11]. TNFa-stimulated gene-6 (TSG-6) is a 35kD glycoprotein that is considered to be a marker of inflammation [20,33]. It is normally absent or produced at very low levels by cells of mesenchymal origin, but they can be induced to secrete TSG-6 when stimulated by TNFa or other proinflammatory mediators such as prostaglandin E 2 and IL-1, both in vitro and in vivo [5,16,20].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it has been suggested recently that TSG-6 can have a protective role against matrix degradation, at least in cartilage, and that transgenic mice that constitutively express TSG-6 in cartilage are more resistant to developing arthritis than control animals [8]. In addition, there is evidence that TSG-6 may form part of a negative feedback loop capable of down-regulating the inflammatory response [7,20,32,33]. In this study we investigated, therefore, whether TSG-6 or IaI was present in normal and diseased intervertebral discs.…”

Section: Introductionmentioning

confidence: 99%

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