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Published ahead of print on June 5, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2009-0110OC
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Submitted on March 30, 2009
Accepted on June 3, 2009

Cytosolic Phospholipase A2 Activation by Candida albicans in Alveolar Macrophages: Role of Dectin-1

Rajinder P Parti1, Robyn Loper1, Gordon D Brown2, Siamon Gordon3, Philip R Taylor4, Joseph V Bonventre5, Robert C Murphy6, David L Williams7, and Christina C Leslie8*

1 Department of Pediatrics, National Jewish Health, Denver, Colorado, United States, 2 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa, 3 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom, 4 Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom, 5 Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, United States, 6 Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, United States, 7 Department of Surgery, James H. Quillen College of Medicine, Johnson City, Tennessee, United States, 8 Department of Pediatrics, National Jewish Health, Denver, Colorado, United States; Departments of Pathology and Pharmacology, University of Colorado Denver, Aurora, Colorado, United States

* To whom correspondence should be addressed. E-mail: lesliec{at}njc.org.

Candida albicans is an increasingly important pulmonary fungal pathogen. Resident alveolar macrophages are important in host defense against opportunistic fungal infections. Activation of Group 1VA cytosolic phospholipase A2{alpha} (cPLA2{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 cPLA2{alpha} in unprimed alveolar macrophages and after priming with 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. 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 cPLA2{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 h 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 cPLA2{alpha} in GM-CSF-primed alveolar macrophages but not in the more delayed phase of AA release and GM-CSF-dependent prostanoid production.
Key words: cytosolic phospholipase A2 • dectin-1 • alveolar macrophages • GM-CSF • Candida albicans






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