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In this study, the involvement of TG2 in monosodium urate (MSU) crystal-induced inflammation was studied.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) were performed to detect TG2 expression in synovial fluid mononuclear cells (SFMCs) and synovial tissue from patients with gouty arthritis. MSU crystal-exposed RAW264.7 mouse macrophages were analyzed for interleukin-1\u03b2 (IL-1\u03b2), tumor necrosis factor-\u03b1 (TNF-\u03b1), transforming growth factor \u03b21 (TGF-\u03b21) and TG2 expression by RT-PCR and enzyme-linked immunosorbent assay (ELISA). TG2 small interfering (si)-RNA-mediated silencing and overexpression in RAW264.7 cells were used to evaluate the involvement of TG2 in resolving MSU crystal-induced inflammation. The role of metastatic tumor antigen 1 (MTA1), a master chromatin modifier, was investigated by MTA1 si-RNA-mediated knockdown. In addition, the inflammatory responses were followed in wild type and TG2 null mice after being challenged with MSU crystals in an in vivo peritonitis model.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>TG2 expression was up-regulated in the synovium tissue and SFMCs from patients with gouty arthritis. The levels of MTA1, TG2, TGF-\u03b21, IL-1\u03b2 and TNF-\u03b1 mRNAs were consistently increased in MSU crystal-stimulated RAW264.7 cells. si-MTA1 impaired the basal, as well as the MSU crystal-induced expression of TG2 and TGF-\u03b21, but increased that of IL-1\u03b2 and TNF-\u03b1. TG2 overexpression dramatically suppressed MSU crystal-induced IL-1\u03b2 and TNF-\u03b1, but significantly enhanced the TGF-\u03b21 production. Neutralizing TGF-\u03b2 antibodies or inhibition of the crosslinking activity of TG2 attenuated these effects. On the contrary, loss of TG2 resulted in a reduced TGF-\u03b2, but in an increased IL-1\u03b2 and TNF-\u03b1 production in MSU crystal-stimulated RAW264.7 cells and mouse embryonic fibroblasts (MEFs). MSU crystal-stimulated IL-1\u03b2 production was Janus kinase 2 (JAK2)-signaling dependent and TG2-induced TGF-\u03b2 suppressed the activity of it. Finally, TG2-deficient mice exhibited hyper inflammatory responses after being challenged with MSU crystals in an <jats:italic>in vivo<\/jats:italic> peritonitis model.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>These findings reveal an inherent regulatory role of the MTA1-TG2 pathway in the self-limitation of MSU crystal-induced inflammation via positively regulating the levels of active TGF-\u03b21 in macrophages that opposes the MSU crystal-induced JAK2-dependent pro-inflammatory cytokine formation.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/s13075-015-0592-7","type":"journal-article","created":{"date-parts":[[2015,3,16]],"date-time":"2015-03-16T17:22:07Z","timestamp":1426526527000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The metastatic tumor antigen 1-transglutaminase-2 pathway is involved in self-limitation of monosodium urate crystal-induced inflammation by upregulating TGF-\u03b21"],"prefix":"10.1186","volume":"17","author":[{"given":"Jia-Hau","family":"Yen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Chung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Chi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Sarang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pui-Ying","family":"Leong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Chang","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeng-Dong","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiunn-Horng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Fan","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pallai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"K\u00f6r\u00f6sk\u00e9nyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsa","family":"Szondy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J","family":"Tsay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,19]]},"reference":[{"key":"592_CR1","doi-asserted-by":"publisher","first-page":"486","DOI":"10.7326\/0003-4819-60-3-486","volume":"60","author":"JM Brill","year":"1964","unstructured":"Brill JM, McCarty DJ. \u201cStudies on the Nature of Gouty Tophi\u201d by Max Freudweiler, 1899. 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