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J. Biol. Chem., Vol. 277, Issue 31, 27887-27895, August 2, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/31/27887    most recent M202998200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schröder, J.-M. Articles by Mallet, A. I. Search for Related Content PubMed PubMed Citation Articles by Schröder, J.-M. Articles by Mallet, A. I. Social Bookmarking                      What's this?

Identification of Diacylated Ureas as a Novel Family of Fungus-specific Leukocyte-activating Pathogen-associated Molecules^*

Jens-Michael Schröder^§¶, Robert Häsler^§, Jörg Grabowsky, Barbara Kahlke, and Anthony I. Mallet

From the  Clinical Research Unit "Cutaneous Inflammation," Department of Dermatology, University Hospital Kiel, Schittenhelmstr. 7, D-24105 Kiel, Germany and the  School of Chemical and Life Sciences, University of Greenwich, SE18 6PF London, United Kingdom

Polymorphonuclear leukocytes represent primary components of the host's innate immune defenses against fungal infection, suggesting involvement of fungal leukocyte attractants. We have found in various fungi, but not in bacteria or host cells, unstable lipid-like leukocyte chemoattractants, which also induced adherence and degranulation in human neutrophils. Purification from bakers' yeast and structural analyses by electrospray mass spectrometry, ¹H NMR spectroscopy, and chemical synthesis revealed these inflammatory mediators as diacylated ureas, a novel class of unstable lipoids. The N,N'-dipalmitoleyl urea appeared to be the most potent innate immune responses inducing compound eliciting half-maximum neutrophil chemotactic activity at 140 nM. The all-trans isomer, N,N'-dipalmitelaidyl urea, was found to be inactive with respect to stimulation of degranulation in neutrophils, which indicates a ₉ cis-double bond to be essential for bioactivity of these diacyl ureas. N,N'-Dipalmitoleyl urea elicited Ca²⁺ mobilization in neutrophils, which was found to be pertussis toxin-sensitive and sensitive toward a carboxylmethyltransferase inhibitor, indicating that these diacyl ureas activate leukocytes via a putative G_i-protein-coupled receptor. Their isolation exclusively from fungi suggests that these lipoids are fungus-specific pathogen-associated molecules that may alert the human innate immunity system to the presence of a fungal infection.

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