Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.

摘要: Objectives 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 TTP via phosphorylation two serine residues. We wished to test hypothesis that these phosphorylations contribute development inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting dephosphorylation activation TTP. Methods expression its relationship with MAPK activity were examined non-inflamed arthritis (RA) tissue. Experimental was induced genetically modified mouse strain, which endogenous cannot phosphorylated inactivated. In vitro vivo experiments performed anti-inflammatory effects compounds activate phosphatase 2A (PP2A) promote Results significantly higher RA than synovium, detected macrophages, vascular endothelial cells some fibroblasts co-localised activation. Substitution sites conferred dramatic protection against mice. Two distinct PP2A agonists also reduced prevented bone erosion. agonism mediated Conclusions state critical determinant responses, tractable target for novel treatments.