Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis.
OBJECTIVE
Recently, Th17 cells, a new subset of CD4+ T cells, emerged as major players in inflammation/autoimmunity. Maintenance of the Th17 phenotype requires interleukin-23 (IL-23), whereas the Th1-promoting cytokine IL-12p70 exerts a negative effect on Th17 cell differentiation. The lipid mediator prostaglandin E(2) (PGE(2)) acts primarily as a proinflammatory agent in autoimmune conditions, through mechanisms that remain to be elucidated. The aim of this study was to investigate whether PGE(2) released in inflammatory foci activates resident dendritic cells (DCs) to express IL-23 (at the expense of IL-12) and IL-6, resulting in a shift toward Th17 cell responses.


METHODS
The effect of PGE(2) on IL-23 production by DCs and subsequent induction of T cell-derived IL-17 was assessed in vitro and in vivo. The effect of the stable PGE analog misoprostol was evaluated in a murine model of rheumatoid arthritis, in conjunction with IL-23 and IL-17 expression in affected joints and draining lymph nodes.


RESULTS
In vivo administration of PGE(2) induced IL-23-dependent IL-17 production. Administration of misoprostol exacerbated collagen-induced arthritis (CIA). CIA exacerbation was associated with increased levels of IL-23p19/p40 messenger RNA and reduced expression of IL-12p35, and with increased levels of the proinflammatory cytokines IL-17, IL-1beta, IL-6, and tumor necrosis factor in the affected joint. Following ex vivo restimulation, draining lymph node cells from misoprostol-treated mice secreted higher levels of IL-17 and lower levels of interferon-gamma.


CONCLUSIONS
Our results indicate that PGE(2) enhances DC-derived IL-6 production and induces a shift in the IL-23/IL-12 balance in favor of IL-23, resulting in increased IL-17 production, presumably through the amplification of self-reactive Th17 cells.
Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
Amir F
AF
Sheibanie
Tanzilya
T
Khayrullina
Fayez F
FF
Safadi
Doina
D
Ganea
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006614:Hindlimb; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016595:Misoprostol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D014033:Toe Joint / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D016595:Misoprostol; D015232:Dinoprostone