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In the present study, we investigated the functional differences between cluster of differentiation (CD)14++CD16− and CD14+CD16+ monocytes during anti- Candida host defense. CD14++CD16− are the 'classical' monocytes and represent the majority of circulating monocytes in humans, while CD14+CD16+ monocytes patrol the vasculature for maintenance of tissue integrity and repair. Both monocyte subsets inhibited the germination of live Candida albicans, and there was no difference in their capacity to phagocytose and kill Candida. Although production of IL-6 and IL-10 induced by C. albicans was found to be similar between monocyte subsets, IL-1β and prostaglandin E2 (PGE2) production was higher in CD14++CD16− compared with CD14+CD16+ monocytes. In line with the increased production of IL-1β and PGE2, central mediators for inducing Th17 responses, CD14++CD16− monocytes induced greater Th17 responses upon stimulation with heat-killed C. albicans yeast. The percentage of cells that expressed mannose receptor (MR) was higher in the CD14++CD16− monocyte subset, and MR-specific stimulation induced higher Th17 responses only in co-cultures of CD14++CD16− monocytes and CD4 lymphocytes. In conclusion, both monocyte subsets have potent innate antifungal properties, but only CD14++CD16− monocytes are capable of inducing a potent Th17 response to C. albicans, an important component of antifungal host defense. [ABSTRACT FROM AUTHOR]

Borrelia burgdorferi spirochetes cause Lyme disease, which can result in severe clinical symptoms such as multiple joint inflammation and neurological disorders. IFN-γ and IL-17 have been suggested to play an important role in the host defense against Borrelia, and in the immunopathology of Lyme disease. The caspase-1-dependent cytokine IL-1β has been linked to the generation of IL-17-producing T cells, whereas caspase-1-mediated IL-18 is crucial for IFN-γ production. In this study, we show by using knockout mice the role of inflammasome-activated caspase-1 in the regulation of cytokine responses by B. burgdorferi. Caspase-1-deficient cells showed significantly less IFN-γ and IL-17 production after Borrelia stimulation . A lack of IL-1β was responsible for the defective IL-17 production, whereas IL-18 was crucial for the IFN-γ production. Caspase-1-dependent IL-33 played no role in the Borrelia-induced production of IL-1β, IFN-γ or IL-17. In conclusion, we describe for the first time the role of the inflammasome-dependent caspase-1 activation of cytokines in the regulation of IL-17 production induced by Borrelia spp. As IL-17 has been implicated in the pathogenesis of chronic Lyme disease, these data suggest that caspase-1 targeting may represent a new immunomodulatory strategy for the treatment of complications of late stage Lyme disease. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines of the IL-1 family play an important role for the anti-mycobacterial host defense mechanisms. In the present study we have deciphered the pathways leading from recognition of Mycobacterium tuberculosis to the production and release of IL-1β, the most important member of the IL-1 family. By stimulating cells defective in various pattern recognition receptors, we could demonstrate that IL-1β production is induced by M. tuberculosis through pathways involving TLR2/TLR6 and NOD2 receptors. In contrast, TLR4, TLR9 and TLR1 receptors are not involved in IL-1β induction. Recognition of M. tuberculosis by TLR and NOD2 leads to transcription of proIL-1β through mechanisms involving ERK, p38 and Rip2, but not JNK. Interestingly, although caspase-1 is necessary for the processing of proIL-1β, activation of caspase-1 is not dependent on the stimulation of cells by M. tuberculosis. Monocytes expressed constitutively active caspase-1. The secretion of IL-1β is dependent on the activation of P2X7-induced pathways by endogenously released ATP. In conclusion, we have dissected the molecular mechanisms responsible for IL-1β production by M. tuberculosis, and that may contribute to a deeper knowledge of the mechanisms of cell activation by M. tuberculosis. [ABSTRACT FROM AUTHOR]

IFN-γ plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-γ production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-γ production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% downmodulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-γ response and promoting the infiltration of the site of infection by monocytes. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the functional differences between cluster of differentiation (CD)14(++) CD16(-) and CD14(+) CD16(+) monocytes during anti-Candida host defense. CD14(++) CD16(-) are the "classical" monocytes and represent the majority of circulating monocytes in humans, while CD14(+) CD16(+) monocytes patrol the vasculature for maintenance of tissue integrity and repair. Both monocyte subsets inhibited the germination of live Candida albicans, and there was no difference in their capacity to phagocytose and kill Candida. Although production of IL-6 and IL-10 induced by C. albicans was found to be similar between monocyte subsets, IL-1β and prostaglandin E2 (PGE2) production was higher in CD14(++) CD16(-) compared with CD14(+) CD16(+) monocytes. In line with the increased production of IL-1β and PGE2, central mediators for inducing Th17 responses, CD14(++) CD16(-) monocytes induced greater Th17 responses upon stimulation with heat-killed C. albicans yeast. The percentage of cells that expressed mannose receptor (MR) was higher in the CD14(++) CD16(-) monocyte subset, and MR-specific stimulation induced higher Th17 responses only in co-cultures of CD14(++) CD16(-) monocytes and CD4 lymphocytes. In conclusion, both monocyte subsets have potent innate antifungal properties, but only CD14(++) CD16(-) monocytes are capable of inducing a potent Th17 response to C. albicans, an important component of antifungal host defense., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)