Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ12,14-Prostaglandin J2 (15d-PGJ2) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4+CD25-FOXP3+ Cells.

Vanessa Carregaro,Larissa G Pinto,Laís Amorim Sacramento,Fernando Q Cunha,Raphael S Peres,Luciana Benevides,Thiago M Cunha,Renata Grespan,Marcelo H Napimoga,João Santana Da Silva

doi:10.1155/2016/9626427

Abstract

The prostaglandin, 15-deoxy Δ12,14-prostaglandin J2 (15d-PGJ2), is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA) is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines. Although the mRNA expression of ROR-γt was profoundly reduced, FOXP3 was enhanced in draining lymph node cells from 15d-PGJ2-treated arthritic mice. The specific and polyclonal CD4+ Th17 cell responses were limited during the addition of prostaglandin to cell culture. Moreover, in vitro 15d-PGJ2 increased the expression of FOXP3, GITR, and CTLA-4 in the CD4+CD25− population, suggesting the induction of Tregs on conventional T cells. Prostanoid addition to CD4+CD25− cells selectively suppressed Th17 differentiation and promoted the enhancement of FOXP3 under polarization conditions. Thus, 15d-PGJ2 ameliorated symptoms of collagen-induced arthritis by regulating Th17 differentiation, concomitant with the induction of Tregs, and, consequently, protected mice from diseases aggravation. Altogether, these results indicate that 15d-PGJ2 may represent a potential therapeutic strategy in RA.

Highlights

Rheumatoid arthritis (RA) is a chronic disorder characterized by chronic systemic inflammation and progressive destruction of cartilage and bone
We investigated whether Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) is expressed during collagen-induced arthritis (CIA), a murine model that shares similarities with rheumatoid arthritis (RA)
Given that the onset and progression of autoimmune diseases (including rheumatoid arthritis (RA)) are mediated by proinflammatory cytokines released into the inflammatory site, we investigated the effect of 15d-PGJ2 treatment upon the production of TNF-α, IFN-γ, IL-17, and IL-12 in affected ankle joints

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic disorder characterized by chronic systemic inflammation and progressive destruction of cartilage and bone. The etiology of RA is unknown, but proinflammatory cytokines play a central role in the disease development and perpetuation [1]. IL-17 is expressed in the synovial tissue of RA patients and animals models and had been implicated in the initiation and progression of arthritis [2]. IL-17 promotes the activation of synovial fibroblasts and both leukocyte emigration and activation, resulting in the production of several inflammatory mediators and tissue lesions. Given the ability of IL-17 to promote RA pathology, it is plausible to suggest that pharmacologic strategies aimed at blocking or suppressing IL-17, cellular Th17 function, may Mediators of Inflammation deserve attention as a potential therapeutic strategy for autoimmune diseases

Methods

Results

Conclusion