The Candida Th 17 response is dependent on mannan-and b-glucan-induced prostaglandin E 2

The fungus Candida albicans is a potent inducer of the Th17 response. Prostaglandin E2 (PGE2) is a strong pro-inflammatory mediator, which has proven to be essential for the Th17 response. In this study, we have investigated the role of PGE2 in the Th17 response induced by C. albicans in humans. PBMC were stimulated with C. albicans in the absence or presence of a non-steroidal antiinflammatory 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 a increased. Stimulation with PGE2 or E prostanoid (EP)2/EP4 agonists restored IL-17 production. Candida albicansmannan 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. b-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 Th17 response induced by C. albicans and that PGE2 is induced by the fungal components mannan and b-glucan that are recognized by the MR and the dectin-1/TLR2 pathway, respectively.