title: Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate Dectin-1-induced inflammatory cytokines.
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.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Karnam
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India. Electronic address: balaji@mcbl.iisc.ernet.in.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000276:immunology*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000276:immunology*; D001231:Aspergillus flavus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D061251:Primary Cell Culture; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000072377:Syk Kinase; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D047071:beta-Glucans / Q000494:pharmacology; D000099181:Dectin-1
chemical_list: D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D053823:Hedgehog Proteins; D018664:Interleukin-12; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C465570:Shh protein, mouse; C038459:curdlan; C077623:Ptgs2 protein, mouse; C546843:mTOR protein, mouse; C000606897:Syk protein, mouse
keywords: C. albicans; COX-2; Curdlan; Dectin-1; Lipoxygenases; Pro-inflammatory cytokines; SHH signaling; mTOR