Schröder Jens-Michael, Häsler Robert, Grabowsky Jörg, Kahlke Barbara, Mallet Anthony I
Clinical Research Unit Cutaneous Inflammation, Department of Dermatology, University Hospital Kiel, Schittenhelmstr. 7, D-24105 Kiel, Germany.
J Biol Chem. 2002 Aug 2;277(31):27887-95. doi: 10.1074/jbc.M202998200. Epub 2002 May 22.
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, (1)H 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 Delta(9) cis-double bond to be essential for bioactivity of these diacyl ureas. N,N'-Dipalmitoleyl urea elicited Ca(2+) 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 Galpha(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.
多形核白细胞是宿主针对真菌感染的固有免疫防御的主要组成部分，这表明真菌白细胞引诱剂参与其中。我们在多种真菌中发现了不稳定的类脂白细胞趋化剂，而在细菌或宿主细胞中未发现，这些趋化剂还能诱导人类中性粒细胞的黏附和脱颗粒。从面包酵母中纯化并通过电喷雾质谱、¹H NMR光谱和化学合成进行结构分析，结果显示这些炎症介质为二酰化脲，这是一类新型的不稳定类脂。N,N'-二棕榈油酰脲似乎是最有效的诱导固有免疫反应的化合物，在140 nM时可引发半数最大中性粒细胞趋化活性。全反式异构体N,N'-二棕榈酰基脲对中性粒细胞脱颗粒的刺激无活性，这表明Δ⁹顺式双键对于这些二酰化脲的生物活性至关重要。N,N'-二棕榈油酰脲在中性粒细胞中引发Ca²⁺动员，发现其对百日咳毒素敏感且对羧甲基转移酶抑制剂敏感，这表明这些二酰化脲通过一种假定的Gα(i)蛋白偶联受体激活白细胞。它们仅从真菌中分离出来，这表明这些类脂是真菌特异性的病原体相关分子，可能会提醒人类固有免疫系统存在真菌感染。
