Disease relevance of TNFAIP6

• TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues [1].
• 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) [2].
• Adenovirus vector-mediated overexpression of TSG-6 inhibited osteoblastic differentiation of human mesenchymal stem cells induced by BMP (bone morphogenetic protein)-2 or OS (osteogenic differentiation medium) [3].
• TSG-6 was low or undetectable in prostate cancer cells (LNCaP, PC-3, and DU145) and TRAMP tumors but up-regulated in response to 2-methoxyestradiol [4].
• The TSG6 cells had well preserved the features of signet-ring cell carcinoma based on morphology [5].

Psychiatry related information on TNFAIP6

• Purification of a hyaluronate-binding protein fraction that modifies cell social behavior [6].

High impact information on TNFAIP6

• The most extensive sequence homology exists between the predicted TSG-6 protein and CD44 [7].
• In contrast, TSG-6 mRNA was undetectable in either control or TNF-treated human vascular endothelial cells and a variety of tumor-derived or virus-transformed cell lines [7].
• The sequence of full-length TSG-6 cDNA revealed one major open reading frame predicting a polypeptide of 277 amino acids, including a typical cleavable signal peptide [7].
• TSG-6 cDNA was isolated by differential screening of a lambda cDNA library prepared from tumor necrosis factor (TNF)-treated human diploid FS-4 fibroblasts [7].
• The NH2-terminal half of the predicted TSG-6 protein sequence shows a significant homology with a region implicated in hyaluronate binding, present in cartilage link protein, proteoglycan core proteins, and the adhesion receptor CD44 [7].

Chemical compound and disease context of TNFAIP6

• Overexpression, purification, and refolding of link module from human TSG-6 in Escherichia coli: effect of temperature, media, and mutagenesis on lysine misincorporation at arginine AGA codons [8].

Biological context of TNFAIP6

• Both TSG-6 and PTX3 are synthesized in the ovary prior to ovulation, where they become components of an expanding viscoelastic matrix that surrounds the oocyte before its release from the follicle at the ovarian surface [9].
• Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14 [9].
• The isolation of the equine TNFAIP6 cDNA revealed that it contains an open reading frame of 834 bp (including the stop codon), encoding a predicted 277 amino acid protein that is highly similar (91-93% identity) to known mammalian homologs [10].
• The regulation of TNFAIP6 mRNA was studied in equine follicles isolated during estrus between 0 and 39 h post-hCG and in corpora lutea (CL) obtained on day 8 of the estrous cycle [10].
• It was hypothesized that this activity of TSG-6 was likely to be mediated by its potentiation of inter-alpha-inhibitor anti-plasmin activity (causing a down-regulation of the protease network), which was reliant on these proteins forming a stable, probably covalent approximately 120-kDa complex [2].

Anatomical context of TNFAIP6

• Analyses performed with isolated preparations of theca and granulosa cells indicated that TNFAIP6 mRNA was regulated in both layers, with a maximal induction obtained 33-36 h post-hCG (P<0.05) [10].
• Large amounts of TSG-6 protein were found in synovial fluids of patients with rheumatoid arthritis [11].
• Using DNA microarrays, we also identified the gene for the hyaluronan-linking protein TSG6 as mechanically induced in smooth muscle cells [12].
• In contrast to the mBSA-injected knee joints of control animals that were heavily damaged from day 5, the cartilage of transgenic mice that constitutively expressed TSG-6 protein remained intact for at least 1 week, and this was followed by a relatively reduced loss of aggrecan [13].
• Role of tumour necrosis factor stimulated gene 6 (TSG-6) in the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human follicular fluid [14].

Associations of TNFAIP6 with chemical compounds

• The extent of expression change of TNFAIP6, an extracellular hyaluronan binding protein, was found to be largely dose-dependent, to respond most strongly to the free acids asiatic acid and madecassic acid, and to increase in expression over 48 hours of treatment [15].
• Western blot analysis with an antiserum raised against a TSG-6 fusion protein detected a 39-kD glycoprotein in the supernatants of TNF-treated FS-4 cells and of cells transfected with TSG-6 cDNA [7].
• The differential effects of HA and heparin on TSG-6 function provide a mechanism for its regulation and functional partitioning in particular tissue microenvironments [16].
• This is likely to involve two transesterification reactions in which an ester bond linking an HC to chondroitin sulfate in intact IalphaI is transferred first onto TSG-6 and then onto HA [17].
• A TSG-6 hydroxyl group reacts with the ester bond between the alpha-carbonyl of the C-terminal Asp residues of HC1 or HC2 and carbon-6 of an internal N-acetylgalactosamine of the chondroitin-4-sulfate chain [18].

Physical interactions of TNFAIP6

• Thus, the local accumulation of TSG-6 protein and TSG-6 protein-bound IalphaI in tsg6/tnfip6 transgenic mice may inhibit serine proteases and subsequent activation of MPs [13].
• TSG-6 also interacts with aggrecan, with a similar pH dependence, and this can be inhibited by HA [19].
• TSG-6 protein forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I alpha I) [11].
• Hyaluronan-linked heavy chains in the extracellular matrix of this cellular complex have recently been shown to be tightly bound to TSG-6 [20].
• TSG-6 can bind to BMP-2 directly and thereby could inhibit BMP-2 signaling [21].

Regulatory relationships of TNFAIP6

• In the present study, an electrophoretic technique by which hyaluronan-bound ITI is immobilized was used to demonstrate that tumour necrosis factor stimulated gene 6 (TSG-6) is necessary for the coupling reaction [14].
• The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan- and inter-alpha -inhibitor-independent manner [2].
• Current topics in pharmacological research on bone metabolism: Promyelotic leukemia zinc finger (PLZF) and tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) identified by gene expression analysis play roles in the pathogenesis of ossification of the posterior longitudinal ligament [21].
• OBJECTIVE: TSG-6 [the product of tumor necrosis factor (TNF)-stimulated gene-6] is a hyaluronan-binding protein that is present in the synovial fluids of arthritis patients and is secreted by cells of articular joints (e.g. chondrocytes and synoviocytes) [22].

Other interactions of TNFAIP6

• Female mice with a targeted disruption of either the TSG-6 or PTX3 gene show severe defects in fertility [9].
• TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo [11].
• RESULTS: Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex [23].
• Real-time PCR showed TNFAIP6 increased by 3.3 folds, while IGFBP5, IGFBP3 decreased by 14 and 11 folds respectively [24].
• In addition, the inhibitory action of TSG-6 and the in vitro interaction of TSG-6 with BMP-2 were abolished by the addition of hyaluronan [3].

Analytical, diagnostic and therapeutic context of TNFAIP6

• Real-time PCR results showed that several genes such as hyaluronan synthase 2 (HAS2), TNF-alpha-induced protein 6 (TNFAIP6) and IL-8 were matched with the array results with statistical significance [25].
• Results from semi-quantitative RT-PCR/Southern blot showed that levels of TNFAIP6 mRNA were low in follicles obtained at 0 h, increased at 12 h, returned to basal levels at 24 h, and increased again at 36 h post-hCG (P<0.05) [10].
• Cartilage-specific constitutive expression of TSG-6 protein was confirmed by in situ hybridization, Western blot analysis, and immunohistochemistry [13].
• Thus, immunoprecipitation of TSG-6 in human follicular fluid eliminates the coupling reaction and re-addition restores the activity [14].
• This study was undertaken to examine the effects of local expression of TSG-6 in arthritic joints of TSG-6 transgenic mice, in the collagen-induced arthritis (CIA) model [26].

References