Meidi Gu;Chuan Ouyang;Wenlong Lin;Ting Zhang;雪涛 曹;Zongping Xia;Xiaojian Wang
Zhejiang University;China Association for Science and Technology
发表时间:2014-3-15
期 刊:Journal of Immunology
语 言:English
U R L: http://www.scopus.com/inward/record.url?scp=84897504553&partnerID=8YFLogxK
The molecular mechanisms that fine tune TLRs responses need to be fully elucidated. Protein phosphatase-1 (PP1) has been shown to be important in cell death and differentiation. However, the roles of PP1 in TLR-triggered immune response remain unclear. In this study, we demonstrate that PP1 inhibits the activation of the MAPK and NF-kB pathway and the production of TNF-a, IL-6 in macrophages triggered by TLR3, TLR4, and TLR9 in a phosphatase-dependent manner. Conversely, PP1 knockdown increases TLRs-triggered signaling and proinflammatory cytokine production. Tautomycetin, a specific inhibitor of PP1, aggravates LPSinduced endotoxin shock in mice. We further demonstrate that PP1 negatively regulates TLR-triggered signaling by targeting TGF-b-activated kinase 1 (TAK1) serine 412 (Ser412) phosphorylation, which is required for activation of TAK1-mediated IL-1R and TLR signaling. Mutation of TAK1 Serine 412 to alanine (S412A) significantly inhibits TLR/IL-1R-triggered NF-kB and MAPK activation and induction of proinflammatory cytokines in macrophage and murine embryonic fibroblast cells. DNA damage-inducible protein 34 (GADD34) specifies PP1 to dephosphorylate TAK1 at Ser412. GADD34 depletion abolished the interaction between TAK1 and PP1, and it relieved PP1 overexpression-induced inhibition of TLRs signaling and proinflammatory cytokine production. In addition, knockdown of GADD34 significantly promotes TLR-induced TAK1 Ser412 phosphorylation, downstream NF-kB and MAPK activation, and proinflammatory cytokine production. Therefore, PP1, as a physiologic inhibitor, together with its regulatory subunit GADD34, tightly controls TLR-induced TAK1 Ser412 phosphorylation, preventing excessive activation of TLRs and protecting the host from overwhelmed inflammatory immune responses. The Journal of Immunology, 2014, 192: 2846-2856.
医学与生命科学
Scopus度量
年份 | CiteScore | SJR | SNIP |
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1996 | |||
1997 | |||
1998 | |||
1999 | 4.568 | 1.6 | |
2000 | 4.272 | 1.508 | |
2001 | 4.302 | 1.521 | |
2002 | 4.601 | 1.505 | |
2003 | 4.409 | 1.476 | |
2004 | 4.227 | 1.45 | |
2005 | 4.328 | 1.458 | |
2006 | 4.382 | 1.381 | |
2007 | 4.655 | 1.379 | |
2008 | 4.609 | 1.315 | |
2009 | 4.157 | 1.339 | |
2010 | 4.165 | 1.306 | |
2011 | 10.4 | 4.06 | 1.347 |
2012 | 10.9 | 4.011 | 1.358 |
2013 | 10.5 | 3.909 | 1.346 |
2014 | 9.6 | 3.744 | 1.264 |
2015 | 9.2 | 3.571 | 1.258 |
2016 | 9.5 | 3.474 | 1.182 |
2017 | 9.2 | 2.837 | 1.118 |
2018 | 8.7 | 2.521 | 1.069 |
2019 | 8.3 | 2.509 | 1.142 |
2020 | 8.4 |
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