Effects of combination of Cryptococcus neoformans and IFN-γ, IL-4 or IL-27 on human bronchial epithelial cells

Abstract The innate immune response and cytokine milieu in the airway mucosa triggered by bronchial epithelial cells are crucial for the establishment or protection of cryptococcosis. In experimental cryptococcosis, Th2 immune response is associated with host susceptibility, while Th1 cells are associated with protection. Additionally, lack of IL-27 receptor alpha increases the Cryptococcus neoformans burden in the lung. Here, we evaluated the effects in vitro of the IL-4, IFN-γ or IL-27 and C. neoformans combination on human bronchial epithelial cells (BEAS-2B). BEAS-2B were stimulated with IL-4, IFN-γ or IL-27 (100  ng/mL) and/or live yeast forms of C. neoformans (multiplicities of infection (MOI) of 1-100). After 24h of infection, IL-6, CCL2 and IL-8 productions and STAT1 and STAT6 phosphorylations were evaluated. We found that cells stimulated with all cytokines (IL-4, IFN-γ or IL-27) followed by C. neoformans infection (MOI of 100) caused a reduction in IL-6 and/or CCL2 production and in STAT6 (induced by IL-4) and STAT1 (induced by IL-27 or IFN-γ) activation when compared to cells stimulated only with C. neoformans, IL-4, IFN-γ or IL-27. In vitro phagocytosis assay showed that the IL-27 and C. neoformans combination decreased the internalized fungus rate, while IL-4 and IFN-γ with C. neoformans favored fungus internalization. Association of C. neoformans with either of these cytokines promoted a higher fungal growth. Our data demonstrate that live yeast forms of C. neoformans with IL-4, IFN-γ or IL-27 induced an anti-inflammatory effect and may lead to a susceptible fungal growth environment in airway epithelium.