Bypassing Pathogen-Induced Inflammasome Activation for the Regulation of Interleukin-1β Production by the Fungal Pathogen Candida albicans

Background. Interleukin (IL)-1 beta has an important role in antifungal defense mechanisms. The inflammasome is thought to be required for caspase-1 activation and processing of the inactive precursor pro-IL-1 beta. The aim of the present study was to investigate the pathways of IL-1 beta production induced by Candida albicans in human monocytes. Methods. Human mononuclear cells were stimulated with C. albicans or mutant strains defective in mannosylation or chitin. Receptors were blocked with specific antagonists, and the IL-1 beta concentration was measured. Results. Human primary monocytes produce bioactive IL-1 beta when stimulated with C. albicans. The transcription of IL-1 beta was induced through mannose receptor (MR), Toll-like receptor (TLR) 2, and dectin-1 but not through TLR4 and TLR9. N-mannan-linked residues, chitin, and beta-glucan from C. albicans are important for IL-1 beta stimulation. Surprisingly, processing and secretion of IL-1 beta in monocytes did not require pathogen-mediated inflammasome activation, because of the constitutive activation of caspase-1 and the capability of monocytes to release endogenous adenosine-5'-triphosphate. Conclusions. This study is the first dissection of the molecular mechanisms of IL-1 beta production by a fungal pathogen. Transcription through mannan/chitin/MR and beta-glucan/dectin-1/TLR2 induces production of IL-1 beta by C. albicans in human monocytes, whereas processing of IL-1 beta is mediated by constitutively active caspase-1.