Cytokine Responses to Fungal Pathogens in Kupffer Cells are Toll‐like Receptor 4 Independent and Mediated by Tyrosine Kinases

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Abstract
Disseminated fungal infections are increasing. However, the interactions between the body's largest population of tissue macrophages, the Kupffer cells and the fungal pathogens are scarcely understood. The aim of this study was to examine the involvement of Toll‐like receptor 4 (TLR4) signalling in cytokine production, using primary cultures of rat and murine Kupffer cells exposed to Aspergillus fumigatus and Candida albicans hyphae and conidia. All fungal components induced the release of tumour necrosis factor‐α (TNF‐α), but with delayed kinetics compared with lipopolysaccharide (LPS). Candida albicans was the most potent inducer of TNF‐α protein and mRNA and the only inducer of interleukin‐10 (IL‐10) in rat Kupffer cells. All fungal components induced enhanced mRNA levels of macrophage inhibitory protein‐2 (MIP‐2) in the cells, similar to LPS. Inhibitors of Src tyrosine kinases added to cells prior to stimulation led to attenuation in the release of both TNF‐α (60%, P < 0.05) and IL‐10 (70%, P < 0.05) induced by C. albicans conidia but did not influence the LPS‐mediated cytokine release. Murine Kupffer cells (C57BL/10J) also released TNF‐α as well as the chemokines keratinocyte‐derived chemokine (KC) and MIP‐2 in response to fungal component. Surprisingly, Kupffer cells from TLR4‐deficient C57BL/ScCr mice exhibited significantly enhanced production of KC and MIP‐2 upon stimulation by fungal components compared with control littermates (P < 0.05). Our study demonstrates that Aspergillus and Candida components induce cytokine production in rat Kupffer cells and that the response to C. albicans conidia involves Src tyrosine kinases. The experiments with TLR4‐deficient Kupffer cells suggest that the cytokine response in these cells to fungal component is not mediated by TLR4.