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Eicosanoid modulation by the short‐chain fatty acid n ‐butyrate in human monocytes
Author(s) -
Kovarik Johannes J.,
Hölzl Markus A.,
Hofer Johannes,
WaidhoferSöllner Petra,
Sobanov Yury,
Koeffel René,
Saemann Marcus D.,
Mechtcheriakova Diana,
Zlabinger Gerhard J.
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12089
Subject(s) - butyrate , eicosanoid , cd14 , biology , lipopolysaccharide , tlr4 , eicosanoid metabolism , short chain fatty acid , leukotriene b4 , inflammation , biochemistry , endocrinology , signal transduction , receptor , immunology , enzyme , fermentation , arachidonic acid
Summary 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 m m 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.