TSG-6, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin.
Nagyeri, Gyorgy, et al.
The Journal of biological chemistry, (2011)
2010
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TSG-6 (TNFα-stimulated gene/protein 6), a hyaluronan (HA)-binding protein, has been implicated in the negative regulation of inflammatory tissue destruction. However, little is known about the tissue/cell-specific expression of TSG-6 in inflammatory processes, due to the lack of appropriate reagents for the detection of this protein in vivo. Here, we report on the development of a highly sensitive detection system and its use in cartilage proteoglycan (aggrecan)-induced arthritis, an autoimmune murine model of rheumatoid arthritis. We found significant correlation between serum concentrations of TSG-6 and arthritis severity throughout the disease process, making TSG-6 a better biomarker of inflammation than any of the other arthritis-related cytokines measured in this study. TSG-6 was present in arthritic joint tissue extracts together with the heavy chains (HCs) of inter-α-inhibitor (IαI). Whereas TSG-6 was broadly detectable in arthritic synovial tissue, the highest level of TSG-6 was co-localized with tryptases in the heparin-containing secretory granules of mast cells. In vitro, TSG-6 formed complexes with the tryptases, murine mast cell protease (mMCP)-6 and mMCP-7 via either heparin or HA. In vivo TSG-6-tryptase association could also be detected in arthritic joint extracts by co-immunoprecipitation, TSG-6 has been reported to suppress inflammatory tissue destruction by enhancing the serine protease inhibitory activity of IαI against plasmin. TSG-6 achieves this by transferring HCs from IαI to HA, thus liberating the active bikunin subunit of IαI. As bikunin is also present in mast cell granules, we propose that TSG-6 can promote inhibition of tryptase activity via a mechanism similar to inhibition of plasmin. | 21566135
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