title: Eicosanoid modulation by the short-chain fatty acid n-butyrate in human monocytes.
abstract: n-Butyrate deriving from bacterial fermentation in the mammalian intestine is a key determinant in gastrointestinal homeostasis. We examined the effects of this short-chain fatty acid and Toll-like receptor 2 (TLR) and TLR4 engagement on inflammatory/immunity-associated genes, cyclo-oxygenases (COXs), prostaglandins (PGs) and leukotrienes (LTs) in human monocytes. Before RNA isolation, freshly isolated human monocytes were co-incubated for different time-points with 1 mm n-butyrate alone or in combination with bacterial stimuli. Based on a knowledge-driven approach, a signature of 180 immunity/inflammation-associated genes was picked and real-time PCR analysis was performed. Pathway analysis was carried out using a web-based database analysing program. Based on these gene expression studies the findings were evaluated at the protein/mediator level by Western blot analysis, FACS and ELISA. Following co-incubation with n-butyrate and lipopolysaccharide, key enzymes of the eicosanoid pathway, like PTGS2 (COX-2), TXS, ALOX5, LTA4H and LTC4S, were significantly up-regulated compared with stimulation with lipopolysaccharide alone. Furthermore, release of the lipid mediators PGE(2), 15d-PGJ(2), LTB(4) and thromboxane B(2) was increased by n-butyrate. Regarding signalling, n-butyrate had no additional effect on mitogen-activated protein kinase and interfered differently with early and late phases of nuclear factor-κB signalling. Our results suggest that among many other mediators of eicosanoid signalling n-butyrate massively induces PGE(2) production by increasing the expression of PTGS2 (COX-2) in monocytes following TLR4 and TLR2 activation and induces secretion of LTB(4) and thromboxane B(2). This underscores the role of n-butyrate as a crucial mediator of gut-specific immunity.
authors: Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors: Johannes J
authors: JJ
authors: Kovarik
authors: Markus A
authors: MA
authors: Hölzl
authors: Johannes
authors: J
authors: Hofer
authors: Petra
authors: P
authors: Waidhofer-Söllner
authors: Yury
authors: Y
authors: Sobanov
authors: René
authors: R
authors: Koeffel
authors: Marcus D
authors: MD
authors: Saemann
authors: Diana
authors: D
authors: Mechtcheriakova
authors: Gerhard J
authors: GJ
authors: Zlabinger
mesh_terms: D002087:Butyrates / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007975:Leukotriene B4 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D013929:Thromboxane B2 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D002087:Butyrates; D015777:Eicosanoids; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007975:Leukotriene B4; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone
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