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

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 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Aspirin triggered-lipoxin A4 reduces the adhesion of human polymorphonuclear neutrophils to endothelial cells initiated by preeclamptic plasma.

INTRODUCTION: Preeclampsia is a disorder of pregnancy, characterized by hypertension and proteinuria after 20 weeks of gestation. Here, we evaluated the role of aspirin triggered-lipoxin A(4) (ATL, 15-epi-LXA(4)) on the modulation of the adhesion of human polymorphonuclear neutrophils (PMN) to endothelial cells initiated by preeclamptic plasma. MATERIALS AND METHODS: Plasma from preeclamptic, normotensive pregnant, and non-pregnant women were analyzed for factors involved in regulating angiogenesis, inflammation and lipid peroxidation. Plasma from preeclamptic women was added to human umbilical vein endothelial cells, and the adhesion of PMN (incubated with or without ATL) to cells was evaluated. RESULTS: Preeclampsia was associated with some augmented anti-angiogenic, oxidative and pro-inflammatory markers, as well as increasing human PMN-endothelial cell adhesion. This cell adhesion was reduced when human PMN were incubated with ATL prior to addition to endothelial monolayers. DISCUSSIONS AND CONCLUSIONS: Our results are the starting point for further research on the efficacy and rational use of aspirin in preeclampsia.

Profiling in resolving inflammatory exudates identifies novel anti-inflammatory and pro-resolving mediators and signals for termination.

A highly orchestrated inflammatory response and its completion, termed resolution, are essential for ongoing health. Thus, complete understanding of the cellular and molecular events that govern natural resolution is vital. Using an unbiased systems approach to profile self-limited inflammatory exudates, we identified a novel genus of specialized pro-resolving lipid mediators (SPMs) comprised of three new families coined the resolvins, protectins and most recently the maresins biosynthesized from omega-3 fatty acids. These join the lipoxin- and aspirin-triggered lipoxins as anti-inflammatory and pro-resolving lipid mediators formed from arachidonic acid with the genus. SPMs have proven stereoselective, and control both the duration and magnitude of inflammation. Mapping these endogenous resolution circuits provides new avenues to probe the molecular basis of many widely occurring diseases where uncontrolled inflammation is characteristic. The focus of this JIM review is to depict recent advances from studies by the authors and colleagues on the biosynthesis and actions of these novel anti-inflammatory, pro-resolving and protective lipid mediators. Together these findings indicate that defective mechanisms and pathways in resolution may underlie our current appreciation of the inflammatory phenotype(s) that characterize some prevalent human diseases.