Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ(12,14)-Prostaglandin J(2) (15d-PGJ(2)) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4(+)CD25(−)FOXP3(+) Cells

The prostaglandin, 15-deoxy Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), 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-PGJ(2) in an experimental model of arthritis. Daily administration of 15d-PGJ(2) attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ(2) 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-PGJ(2)-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-PGJ(2) 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-PGJ(2) 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-PGJ(2) may represent a potential therapeutic strategy in RA.