Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein that in humans is encoded by the TNFAIP6 (tumor necrosis factor, alpha-induced protein 6) gene.
TSG-6 is a 30 kDa secreted protein that contains a hyaluronan-binding LINK domain a and thus is a member of the hyaluronan-binding protein family, also called hyaladherins. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. This protein has been shown to form a stable, covalent complex with inter-alpha-inhibitor (IαI), and thus enhance the serine protease inhibitory activity of IαI, which is important in the protease network associated with inflammation. The expression of this gene can be induced by a number of signalling molecules, principally tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The expression can also be induced by mechanical stimuli in vascular smooth muscle cells, and is found to be correlated with proteoglycan synthesis and aggregation. TSG-6 has been shown to modulate macrophage plasticity and signal the transition of LPS-treated macrophages from pro- to anti-inflammatory phenotype.
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Parkar AA, Kahmann JD, Howat SL, Bayliss MT, Day AJ (May 1998). "TSG-6 interacts with hyaluronan and aggrecan in a pH-dependent manner via a common functional element: implications for its regulation in inflamed cartilage". FEBS Letters. 428 (3): 171–6. doi:10.1016/S0014-5793(98)00523-7. PMID9654129.
Lee RT, Yamamoto C, Feng Y, Potter-Perigo S, Briggs WH, Landschulz KT, Turi TG, Thompson JF, Libby P, Wight TN (April 2001). "Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells". The Journal of Biological Chemistry. 276 (17): 13847–51. doi:10.1074/jbc.M010556200. PMID11278699.
Nentwich HA, Mustafa Z, Rugg MS, Marsden BD, Cordell MR, Mahoney DJ, Jenkins SC, Dowling B, Fries E, Milner CM, Loughlin J, Day AJ (May 2002). "A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression". The Journal of Biological Chemistry. 277 (18): 15354–62. doi:10.1074/jbc.M110765200. PMID11854277.
Getting SJ, Mahoney DJ, Cao T, Rugg MS, Fries E, Milner CM, Perretti M, Day AJ (December 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. 277 (52): 51068–76. doi:10.1074/jbc.M205121200. PMID12401803.
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Sanggaard KW, Karring H, Valnickova Z, Thøgersen IB, Enghild JJ (March 2005). "The TSG-6 and I alpha I interaction promotes a transesterification cleaving the protein-glycosaminoglycan-protein (PGP) cross-link". The Journal of Biological Chemistry. 280 (12): 11936–42. doi:10.1074/jbc.M409016200. PMID15653696.
Blundell CD, Almond A, Mahoney DJ, DeAngelis PL, Campbell ID, Day AJ (May 2005). "Towards a structure for a TSG-6.hyaluronan complex by modeling and NMR spectroscopy: insights into other members of the link module superfamily". The Journal of Biological Chemistry. 280 (18): 18189–201. doi:10.1074/jbc.M414343200. PMID15718240.
Mindrescu C, Le J, Wisniewski HG, Vilcek J (May 2005). "Up-regulation of cyclooxygenase-2 expression by TSG-6 protein in macrophage cell line". Biochemical and Biophysical Research Communications. 330 (3): 737–45. doi:10.1016/j.bbrc.2005.03.040. PMID15809059.