<scp>TGR</scp>5 signalling inhibits the production of pro‐inflammatory cytokines by <i>in vitro</i> differentiated inflammatory and intestinal macrophages in Crohn's disease

<jats:title>Summary</jats:title><jats:p>Bile acids (<jats:styled-content style="fixed-case">BA</jats:styled-content>s) play important roles not only in lipid metabolism, but also in signal transduction. <jats:styled-content style="fixed-case">TGR</jats:styled-content>5, a transmembrane receptor of <jats:styled-content style="fixed-case">BA</jats:styled-content>s, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how <jats:styled-content style="fixed-case">BA</jats:styled-content>s operate in immunological responses via the <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 pathway in human mononuclear cell lineages. We examined <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 expression in human peripheral blood monocytes, several types of <jats:italic>in vitro</jats:italic> 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 <jats:styled-content style="fixed-case">CD</jats:styled-content>14<jats:sup>+</jats:sup> Mϕs that contribute to Crohn's disease (<jats:styled-content style="fixed-case">CD</jats:styled-content>) pathogenesis by production of pro‐inflammatory cytokines, highly expressed <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 agonist and two types of <jats:styled-content style="fixed-case">BA</jats:styled-content>s, 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 <jats:styled-content style="fixed-case">TGR</jats:styled-content>5–<jats:styled-content style="fixed-case">cAMP</jats:styled-content> pathway to induce phosphorylation of c‐<jats:styled-content style="fixed-case">F</jats:styled-content>os that regulated nuclear factor‐κ<jats:styled-content style="fixed-case">B</jats:styled-content> p65 activation. Next, we analysed <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 levels in lamina propria mononuclear cells (<jats:styled-content style="fixed-case">LPMC</jats:styled-content>s) obtained from the intestinal mucosa of patients with <jats:styled-content style="fixed-case">CD</jats:styled-content>. Compared with non‐inflammatory bowel disease, inflamed <jats:styled-content style="fixed-case">CD LPMC</jats:styled-content>s contained more <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 transcripts. Among <jats:styled-content style="fixed-case">LPMC</jats:styled-content>s, isolated <jats:styled-content style="fixed-case">CD</jats:styled-content>14<jats:sup>+</jats:sup> intestinal Mϕs from patients with <jats:styled-content style="fixed-case">CD</jats:styled-content> expressed <jats:styled-content style="fixed-case">TGR</jats:styled-content>5. In isolated intestinal <jats:styled-content style="fixed-case">CD</jats:styled-content>14<jats:sup>+</jats:sup> Mϕs, a <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 agonist could inhibit tumour necrosis factor‐α production. These results indicate that <jats:styled-content style="fixed-case">TGR</jats:styled-content>5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.</jats:p>