title: Cytosolic phospholipase a2 activation by Candida albicans in alveolar macrophages: role of dectin-1.
abstract: Candida albicans is an increasingly important pulmonary fungal pathogen. Resident alveolar macrophages are important in host defense against opportunistic fungal infections. Activation of Group IVA cytosolic phospholipase A(2)alpha (cPLA(2)alpha) in macrophages initiates arachidonic acid (AA) release for production of eicosanoids, which regulate inflammation and immune responses. We investigated the ability of C. albicans to activate cPLA(2)alpha in unprimed alveolar macrophages and after priming with granulocyte macrophage colony-stimulating factor (GM-CSF), which regulates alveolar macrophage maturation. AA was released within minutes by GM-CSF-primed but not unprimed alveolar macrophages in response to C. albicans, and was blocked by soluble glucan phosphate (S-GP). The expression of the beta-glucan receptor dectin-1 was increased in GM-CSF-primed macrophages, and AA release from GM-CSF-primed dectin-1(-/-) alveolar macrophages was reduced to basal levels. The enhanced activation of extracellular signal-regulated kinases and phosphorylation of cPLA(2)alpha on Ser-505 that occurred in GM-CSF-primed macrophages were reduced by MEK1 and Syk inhibitors, which also suppressed AA release. At later times after C. albicans infection (6 h), unprimed and GM-CSF-primed macrophages released similar levels of AA. The expression of cyclooxygenase 2 and prostanoid production at 6 hours was higher in GM-CSF-primed macrophages, but the responses were not dependent on dectin-1. However, dectin-1 contributed to the C. albicans-stimulated increase in TNF-alpha production that occurred in GM-CSF-primed macrophages. The results demonstrate that dectin-1 mediates the acute activation of cPLA(2)alpha in GM-CSF-primed alveolar macrophages, but not in the more delayed phase of AA release and GM-CSF-dependent prostanoid production.
authors.affiliation: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, CO 80206, USA.
authors.forename: Rajinder P
authors.initials: RP
authors.lastname: Parti
authors.forename: Robyn
authors.initials: R
authors.lastname: Loper
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Christina C
authors.initials: CC
authors.lastname: Leslie
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000276:immunology* / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1 / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D016718:Arachidonic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054513:Group IV Phospholipases A2; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha; D000099181:Dectin-1; C000606897:Syk protein, mouse; C482127:Map2k1 protein, mouse