Interleukin-27 inhibits phagosomal acidification by blocking vacuolar ATPases

•The anti-inflammatory nature of IL-27 includes interference with lysosomes.•IL-27 inhibits phagosomal acidification.•IL-27 decreases the expression of vacuolar ATPase (V-ATPase).•IL-27 influence on lysosomal acidification compromises control of bacterial growth. Interleukin (IL)-27 is a unique cytokine that has a dual role in immune responses. It was originally described to promote Th1 differentiation but also suppresses inflammation by inhibiting these and other inflammatory T cell subsets. Inhibition of inflammatory activity in macrophages has also been reported. These reports have largely focused on cytokine profiles or signaling mechanisms. To date, there have been no reports of how IL-27 may directly influence cellular mechanisms that operate to control microbial growth. Formation of a phagolysosome that acquires antimicrobial properties is an essential step for destruction of pathogens or pathogen-derived materials that are internalized by macrophages. Here we report that IL-27 has a profound influence on this critical innate immunity pathway. Treatment of human macrophages with IL-27 interferes with the acidification of phagosomes by reducing protein levels of V-ATPase and impairs control of bacterial pathogens.