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

Karnam, Anupama and Holla, Sahana and Balaji, Kithiganahalli Narayanaswamy (2015) Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate Dectin-1-induced inflammatory cytokines. In: MOLECULAR IMMUNOLOGY, 68 (2, A). pp. 280-289.

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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-l-responsive pro-inflammatory signature cytokines like TNE-alpha, IL-1 beta 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. (C) 2015 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Publication:	MOLECULAR IMMUNOLOGY
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Additional Information:	Copy right for this article belongs to the PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Keywords:	Dectin-1; C. albicans; Curdlan; mTOR; SHH signaling; Lipoxygenases; COX-2; Pro-inflammatory cytokines
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	20 Jan 2016 05:08
Last Modified:	20 Jan 2016 05:08
URI:	http://eprints.iisc.ac.in/id/eprint/53150

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