Abstract
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.
Highlights
The immune system is intricately constituted to maintain homeostasis and avoid excessive or deficient responses against foreign antigens, which causes immunological disorders
We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (M/s) and dendritic cells
M/s differentiated with macrophage colony-stimulating factor and interferon-c (Mc-M/s), which are similar to the human intestinal lamina propria CD14+ M/s that contribute to Crohn’s disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated M/ and dendritic cells
Summary
The immune system is intricately constituted to maintain homeostasis and avoid excessive or deficient responses against foreign antigens, which causes immunological disorders. The study showed that M/s have several subpopulations[1,2] that were classified broadly into two categories: an inflammatory phenotype that is stimulated to produce pro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a) or an anti-inflammatory phenotype that induces immune tolerance by producing interleukin-10 (IL-10). Intestinal M/s play a role in the maintenance of immunological homeostasis by regulation of some inflammatory cytokines against foreign antigens such as commensal bacteria, even if phagocytic and bactericidal activity remains.[2,3] We previously reported that mouse intestinal M/s produce IL-10 in response to bacterial stimulation, which prevents an excess immune response.[4] we identified that there are two subsets of resident mouse intestinal M/s, and monocyte chemoattractant protein-1 is important for the composition of IL-10producing intestinal M/s.5. We identified that there are two subsets of resident mouse intestinal M/s, and monocyte chemoattractant protein-1 is important for the composition of IL-10producing intestinal M/s.5 Denning et al.[6] reported that intestinal M/s can induce regulatory T cells
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