Eicosanoid modulation by the short-chain fatty acid n-butyrate in human monocytes

Authors

  • Johannes J. Kovarik,

    Corresponding author
    1. Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
    • Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Markus A. Hölzl,

    1. Division of Transplantation Immunology, Children's Cancer Research Institute, Vienna, Austria
    Search for more papers by this author
  • Johannes Hofer,

    1. Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Petra Waidhofer-Söllner,

    1. Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Yury Sobanov,

    1. Institute of Pathophysiology and Allergy Research IPA, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • René Koeffel,

    1. Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Marcus D. Saemann,

    1. Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Diana Mechtcheriakova,

    1. Institute of Pathophysiology and Allergy Research IPA, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author
  • Gerhard J. Zlabinger

    Corresponding author
    • Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
    Search for more papers by this author

Correspondence: Gerhard J. Zlabinger, Institute of Immunology, Centre of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria. Email: gerhard.zlabinger@meduniwien.ac.at

Senior author: Gerhard J. Zlabinger

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 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 PGE2, 15d-PGJ2, LTB4 and thromboxane B2 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 PGE2 production by increasing the expression of PTGS2 (COX-2) in monocytes following TLR4 and TLR2 activation and induces secretion of LTB4 and thromboxane B2. This underscores the role of n-butyrate as a crucial mediator of gut-specific immunity.

Ancillary