Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ^12,14-Prostaglandin J₂(15d-PGJ₂) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4⁺CD25⁻FOXP3⁺Cells

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.

Systemic treatment with resveratrol reduces the progression of experimental periodontitis and arthritis in rats

“…The bidirectional relationship between both diseases has been investigated and studies have showed increase in gingival inflammatory status in the presence of RA [ 9 – 11 ], as well as the increasing of RA occurrence and severity in a periodontitis condition [ 20 ]. Considering this, immunomodulation has been a therapeutic approach evaluated [ 21 ] for both diseases, especially focusing on natural products [ 22 – 28 ].…”

15d-PGJ2-loaded nanocapsules ameliorate experimental gout arthritis by reducing pain and inflammation in a PPAR-gamma-sensitive manner in mice

“…As 15d-PGJ 2 is an endogenous regulator of PPAR-γ 7 and activation of this ligand-activated transcription factor has been shown to have analgesic properties 15 , 24 , we next evaluated whether the effect of 15d-PGJ 2 -loaded NC occurred in a PPAR-γ-sensitive manner. To this end, it was used GW9662 (i.art., 30 min before MSU injection, 3–30 ng per joint), a selective and irreversible antagonist of PPAR-γ 25 .…”

“…Activation of PPAR-γ has been shown to induce analgesia and to drive active resolution of inflammation in varied experimental models 14 , 15 , 24 , 32 , 33 . Topical treatment with 15d-PGJ 2 reduces temporomandibular joint pain in rats 16 .…”

“…In addition to resolve inflammation, activation of PPAR-γ by other molecules also induces analgesia 13 , 14 , which indicates that activating this nuclear receptor represents a promising analgesic approach. In fact, treatment with 15d-PGJ 2 reduces temporomandibular joint pain 15 – 18 . Interestingly, nanoencapsulated 15d-PGJ 2 requires a dose 33 times lower to inhibit inflammation 19 and pain compared to the effects of free 15d-PGJ 2 (30 μg/kg vs .…”

“…Interestingly, nanoencapsulated 15d-PGJ 2 requires a dose 33 times lower to inhibit inflammation 19 and pain compared to the effects of free 15d-PGJ 2 (30 μg/kg vs . 1000 μg/kg) 15 . Nanocapsules consist of polymeric involucres around a nucleus generally oily used to prolong pharmacological activity and decrease toxicity of molecules 20 .…”