Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into themechanisms by which this wormsuppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identifiedthis compoundasprostaglandin(PG)E2.Thepurifiedcompoundshowedsimilarproperties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and inmodulating Rab7Band P2RX7 expression in human DCs. Furthermore, theTsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipidmediators as establishedbymetabololipidomic analysis.Culture of T. suiswith several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that theworms can synthesize PGE2 via aCOX-independent pathway.Weconclude that T. suis secretesPGE2to suppress proinflammatory responses inhumanDCs, therebymodulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S.M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J. 31, 719-731 (2017). www.fasebj.org.