TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease.

Authors:
Kazuaki Yoneno
Kazuaki Yoneno
School of Medicine
Japan
Tadakazu Hisamatsu
Tadakazu Hisamatsu
School of Medicine
Japan
Katsuyoshi Shimamura
Katsuyoshi Shimamura
Keio University School of Medicine
Japan
Nobuhiko Kamada
Nobuhiko Kamada
University of Michigan Medical School
United States
Riko Ichikawa
Riko Ichikawa
School of Medicine
Mina T Kitazume
Mina T Kitazume
School of Medicine
Maiko Mori
Maiko Mori
Karolinska University Hospital Huddinge
Michihide Uo
Michihide Uo
Research Institute

Immunology 2013 May;139(1):19-29

Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14(+) Mϕs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14(+) Mϕs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.

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http://dx.doi.org/10.1111/imm.12045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634536PMC

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May 2013
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References

(Supplied by CrossRef)
Monocyte and macrophage heterogeneity
Gordon et al.
Nat Rev Immunol 2005
Inflammatory bowel disease
Abraham et al.
N Engl J Med 2009
Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis
Kamada et al.
J Clin Invest 2008

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