The Candida Th17 response is dependent on mannan- and beta-glucan-induced prostaglandin E2.
The fungus Candida albicans is a potent inducer of the T(h)17 response. Prostaglandin E2 (PGE2) is a strong pro-inflammatory mediator, which has proven to be essential for the T(h)17 response. In this study, we have investigated the role of PGE2 in the T(h)17 response induced by C. albicans in humans. PBMC were stimulated with C. albicans in the absence or presence of a non-steroidal anti-inflammatory drug (NSAID). In separate experiments, PGE2 or the prostlaglandin receptors agonists butaprost or misoprostol were added to the cells. PBMC were also stimulated with fungal components and small interfering RNA for mannose receptor (MR) was performed. PGE2 and cytokines were measured by ELISA or luminex, and the source of IL-17 production was determined using FACS analysis. Blocking Candida-induced PGE2 production by an NSAID resulted in decreased IL-17 and IL-22 production and inhibited expression of RAR-related orphan receptor gamma T mRNA. Furthermore, when PGE2 production was blocked, IL-6, IL-23 and IL-10 were decreased, while tumor necrosis factor α increased. Stimulation with PGE2 or E prostanoid (EP)2/EP4 agonists restored IL-17 production. Candida albicans mannan was the only fungal component that was able to directly induce PGE2 and silencing of the MR resulted in a reduction of Candida-induced PGE2. β-Glucan engagement of dectin-1 synergistically increased Toll-like receptor 2 (TLR2)-induced PGE2 production. These data provide evidence that PGE2 pathway is important for the T(h)17 response induced by C. albicans and that PGE2 is induced by the fungal components mannan and β-glucan that are recognized by the MR and the dectin-1/TLR2 pathway, respectively.
Department of Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands.
Sanne P
SP
Smeekens
Frank L
FL
van de Veerdonk
Jos W M
JW
van der Meer
Bart Jan
BJ
Kullberg
Leo A B
LA
Joosten
Mihai G
MG
Netea
D002176:Candida albicans / Q000166:cytology / Q000276:immunology*; D015232:Dinoprostone / Q000378:metabolism*; D008351:Mannans / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D047071:beta-Glucans / Q000276:immunology*
D008351:Mannans; D047071:beta-Glucans; D015232:Dinoprostone