Abstract
Immune responses during fungal infections are predominately mediated by 5/15-lipoxygenases (LO)- or cyclooxygenase (COX)-2-catalysed bioactive eicosanoid metabolites like leukotrienes, lipoxins and prostaglandins. Although few host mediators of fungi-triggered eicosanoid production have been established, the molecular mechanism of expression and regulation of 5-LO, 15-LO and COX-2 are not well-defined. Here, we demonstrate that, macrophages infected with representative fungi Candida albicans, Aspergillus flavus or Aspergillus fumigatus or those treated with Curdlan, a selective agonist of pattern recognition receptor for fungi Dectin-1, displays increased expression of 5-LO, 15-LO and COX-2. Interestingly, Dectin-1-responsive Syk pathway activates mTOR-sonic hedgehog (SHH) signaling cascade to stimulate the expression of these lipid metabolizing enzymes. Loss-of-function analysis of the identified intermediaries indicates that while Syk-mTOR-SHH pathway-induced 5-LO and 15-LO suppressed the Dectin-1-responsive pro-inflammatory signature cytokines like TNF-α, IL-1β and IL-12, Syk-mTOR-SHH-induced COX-2 positively regulated these cytokines. Dectin-1-stimulated IL-6, however, is dependent on 5-LO, 15-LO and COX-2 activity. Together, the current study establishes Dectin-1-arbitrated host mediators that direct the differential regulation of immune responses during fungal infections and thus are potential candidates of therapeutic intervention.
Keywords:
C. albicans; COX-2; Curdlan; Dectin-1; Lipoxygenases; Pro-inflammatory cytokines; SHH signaling; mTOR.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arachidonate 15-Lipoxygenase / genetics
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Arachidonate 15-Lipoxygenase / immunology*
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Arachidonate 5-Lipoxygenase / genetics
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Arachidonate 5-Lipoxygenase / immunology*
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Aspergillus flavus / drug effects
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Aspergillus flavus / growth & development
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Aspergillus flavus / immunology
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Aspergillus fumigatus / drug effects
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Aspergillus fumigatus / growth & development
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Aspergillus fumigatus / immunology
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Candida albicans / drug effects
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Candida albicans / growth & development
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Candida albicans / immunology
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Cell Line
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / immunology*
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Gene Expression Regulation
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Hedgehog Proteins / genetics
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Hedgehog Proteins / immunology*
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Host-Pathogen Interactions
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Interleukin-12 / biosynthesis
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Interleukin-12 / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Lectins, C-Type / agonists
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / microbiology
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Mice
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Primary Cell Culture
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / immunology
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Signal Transduction
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Syk Kinase
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / immunology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
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beta-Glucans / pharmacology
Substances
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Hedgehog Proteins
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Lectins, C-Type
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Shh protein, mouse
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Tumor Necrosis Factor-alpha
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beta-Glucans
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dectin 1
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Interleukin-12
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curdlan
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Arachidonate 15-Lipoxygenase
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Arachidonate 5-Lipoxygenase
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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mTOR protein, mouse
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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TOR Serine-Threonine Kinases