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

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.

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

“…As the b-ZIP domain of LAP has been reported to interact with the Rel homology domain of NF-κB and to enhance NF-κB-dependent transcription (82)(83)(84)(85), the dominant-negative C/EBPβ isoform LIP could also blunt NF-κB activation and further decrease the inflammatory response. Several studies demonstrate that TGR5 activation inhibits NF-κB signaling through pleiotropic mechanisms, including IκBα, CREB, and c-Fos phosphorylation (32,34,36). Our present data add modulation of LIP translation to the means by which TGR5 could reduce the inflammatory actions of NF-κB.…”

“…TGR5 is also expressed in cells of the hematopoietic system, such as monocytes and macrophages, and confers potent antiinflammatory properties in vitro and in vivo (31)(32)(33)(34)(35)(36). Recent work from our laboratory revealed that the immune-suppressive actions of TGR5 in macrophages contribute to the prevention of the atherosclerotic process (34).…”

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

“…Moreover, effects in dog occurred at concentrations overlapping with the IC 50 values for inhibition of human TNF-a and IL-12p40 production (in vitro functional indices of efficacy) and, for BIX02694, at near-therapeutic concentrations in a preclinical DNBS efficacy model suggesting an inability to separate GPBAR1-mediated efficacy and ontarget cardiovascular liabilities in vivo and that resulted in termination of the project. GPBAR1 signaling in myeloid cells leads to downregulation of responses to proinflammatory stimuli in primary human macrophages in vitro (Haselow et al, 2013;Yoneno et al, 2013) and reductions in inflammation in vivo via genetic approaches in which knockout mice are more susceptible to inflammation (Wang et al, 2011), including injury-induced colitis (Cipriani et al, 2011), or in which receptor agonists offer protection from colitis and other inflammatory models (Martín et al, 2010;Cipriani et al, 2011;Pols et al, 2011a). In colitis, the improvement in the clinical score appears to be linked to a direct impact on monocyte infiltration into the colon, consistent with the importance of these cells in disease pathology.…”

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…The anti-inflammatory function of TGR5 in protection against IBD is mediated by inhibition of NF-kB-dependent proinflammatory cytokine production. It was demonstrated that a TGR5 selective agonist protected the integrity of intestinal barrier function, immune response, and proinflammatory cytokine production in experimental colitis models (Cipriani et al, 2011;Yoneno et al, 2013).…”