Ross E A, Naylor A J, O'Neil J D, Crowley T, Ridley M L, Crowe J, Smallie T, Tang T J, Turner J D, Norling L V, Dominguez S, Perlman H, Verrills N M, Kollias G, Vitek M P, Filer A, Buckley C D, Dean J L, Clark A R
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
Ann Rheum Dis. 2017 Mar;76(3):612-619. doi: 10.1136/annrheumdis-2016-209424. Epub 2016 Sep 5.
Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.
The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.
TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.
The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.
锌指蛋白36（TTP）是多种促炎基因的负调节因子，在类风湿性滑膜细胞中高表达。丝裂原活化蛋白激酶（MAPK）p38信号通路通过使TTP的两个丝氨酸残基磷酸化来介导其失活。我们希望验证以下假设：这些磷酸化作用促进了炎性关节炎的发展，相反，通过促进TTP的去磷酸化和激活可以抑制关节炎症。
在非炎性和类风湿性关节炎（RA）滑膜组织中检测TTP的表达及其与MAPK p38活性的关系。在一种基因改造的小鼠品系中诱导实验性关节炎，该品系中内源性TTP不能被磷酸化和失活。进行体外和体内实验以测试激活蛋白磷酸酶2A（PP2A）并促进TTP去磷酸化的化合物的抗炎作用。
RA中TTP的表达显著高于非炎性滑膜，在巨噬细胞、血管内皮细胞和一些成纤维细胞中检测到，并且与MAPK p38的激活共定位。TTP磷酸化位点的取代赋予小鼠对炎性关节炎的显著保护作用。两种不同的PP2A激动剂也减轻了炎症并防止了骨侵蚀。PP2A激动剂的体外抗炎作用是由TTP激活介导的。
TTP的磷酸化状态是炎症反应的关键决定因素，也是新型抗炎治疗的可控靶点。
