Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate dectin-1-induced inflammatory cytokines

Karnam, Anupama ; Holla, Sahana ; Balaji, Kithiganahalli Narayanaswamy (2015) Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate dectin-1-induced inflammatory cytokines Molecular Immunology, 68 (2). pp. 280-289. ISSN 0161-5890

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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.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:Dectin-1; C. albicans; Curdlan; mTOR; SHH Signaling; Lipoxygenases; COX-2; Pro-inflammatory Cytokines
ID Code:99563
Deposited On:26 Nov 2016 11:58
Last Modified:26 Nov 2016 11:59

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