title: Exogenous farnesol interferes with the normal progression of cytokine expression during candidiasis in a mouse model.
abstract: Candida albicans, a dimorphic fungus composed of yeast and mycelial forms, is the most common human fungal pathogen. Th1 cytokines such as interleukin-2 (IL-2), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), which are induced by macrophage IL-12, are critical to resistance against systemic candidiasis, while Th2 cytokines such as IL-4 and IL-5 are less critical. Farnesol is a quorum-sensing molecule produced by C. albicans that controls the formation of mycelia but is also a virulence factor. To determine whether farnesol enhances the virulence of C. albicans by modulating the production of Th1 and Th2 cytokines, mice were pretreated with farnesol prior to intravenous infection with a sublethal dose of farnesol-producing C. albicans. Production of IL-2, IL-4, IL-5, TNF-alpha, IFN-gamma, and IL-12 was evaluated by bead-array flow cytometry and enzyme-linked immunosorbent assay. Mice exhibited an elevation in serum TNF-alpha levels at 48 h and an elevation in IFN-gamma and IL-12 levels at 6 to 12 h after infection with C. albicans. Pretreatment with farnesol significantly reduced the elevation of both IFN-gamma and IL-12 but not TNF-alpha. In contrast, mice pretreated with farnesol exhibited an unexpected elevation in IL-5 levels. To determine whether farnesol has a direct effect on macrophage production of IL-12, peritoneal macrophages were pretreated with farnesol prior to stimulation with IFN-gamma plus lipopolysaccharide (LPS). Farnesol inhibited production of both IL-12 p40 and p70 from IFN-gamma/LPS-stimulated macrophages. Therefore, the role of farnesol in systemic candidiasis is likely due to its ability to inhibit the critical Th1 cytokines IFN-gamma and IL-12 and perhaps to enhance a Th2 cytokine, IL-5.
authors.affiliation: Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583, USA.
authors.forename: Dhammika H M L P
authors.initials: DH
authors.lastname: Navarathna
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Nickerson
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Duhamel
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jerrels
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Petro
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005204:Farnesol / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D016207:Cytokines; D037521:Virulence Factors; D005204:Farnesol