title: 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.
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-PGJ2in an experimental model of arthritis. Daily administration of 15d-PGJ2attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2treatment 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 vitro15d-PGJ2increased 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-PGJ2ameliorated 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-PGJ2may represent a potential therapeutic strategy in RA.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Vanessa
authors.identifier: 0000-0002-8435-0766
authors.initials: V
authors.lastname: Carregaro
authors.affiliation: Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, 13045755 Campinas, SP, Brazil.
authors.forename: Marcelo H
authors.identifier: 0000-0003-4472-365X
authors.initials: MH
authors.lastname: Napimoga
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Raphael S
authors.identifier: 0000-0002-0417-779X
authors.initials: RS
authors.lastname: Peres
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Benevides
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Laís Amorim
authors.identifier: 0000-0003-1987-8369
authors.initials: LA
authors.lastname: Sacramento
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Pinto
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Renata
authors.identifier: 0000-0003-3644-7632
authors.initials: R
authors.lastname: Grespan
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: João Santana
authors.identifier: 0000-0002-3410-3927
authors.initials: JS
authors.lastname: da Silva
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil; Department of Pharmacology, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Fernando Q
authors.identifier: 0000-0003-4755-1670
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058504:Th17 Cells / Q000187:drug effects* / Q000378:metabolism*
chemical_list: C477819:15-deoxyprostaglandin J2; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D047495:PPAR gamma; D015230:Prostaglandin D2