title: Prostaglandin E2 suppresses antifungal immunity by inhibiting interferon regulatory factor 4 function and interleukin-17 expression in T cells.
abstract: T helper 17 (Th17) cells play an important role in mucosal host defense through production of the signature cytokines IL-17 and IL-22. Prostaglandin E2 (PGE2) has been shown to enhance IL-17 production by mature Th17 cells. However, when present during Th17 cell differentiation, we found that PGE2 inhibited the transcription factor IRF4 and suppressed production of IL-17 but not IL-22. We show that IRF4 was required for IL-17 expression but inhibited IL-22 expression, highlighting the potential for discordant regulation of these two cytokines in Th17 cells. The pathogenic fungus Cryptococcus neoformans produces PGE2, and we found that it uses PGE2- and IRF4-dependent mechanisms to specifically inhibit induction of IL-17 during Th17 cell differentiation. Blockade of host PGE2 during infection led to increased IL-17 production from CD4(+) T cells and increased survival of mice. These findings suggest that host- or pathogen-derived PGE2 can act directly on Th17 cells during differentiation to inhibit IL-17-dependent antimicrobial responses.
authors.affiliation: Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Valdez
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Vithayathil
authors.forename: Brian M
authors.initials: BM
authors.lastname: Janelsins
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000276:immunology; D003455:Cryptococcus neoformans / Q000378:metabolism* / Q000472:pathogenicity; D015232:Dinoprostone / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D000097043:Interleukin-22; D000099218:Interferon Regulatory Factor-4
chemical_list: D015232:Dinoprostone; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22; D000099218:Interferon Regulatory Factor-4