Maiko Mori

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

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 Crohns 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.

Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation

Background Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. Objective To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. Methods We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcγR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. Results IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19+CD27low, CCR10lowCXCR4high) compared with IgA plasma cells (CD19+/−CD27high, CCR10highCXCR4−/low). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1β (IL-1β), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1β production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. Conclusions Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of ‘pathogenic’ intestinal CD14 macrophages via IgG-IC-FcγR signalling.

The performance of a novel amino acid multivariate index for detecting lung cancer: A case control study in Korea

INTRODUCTION Previous studies have shown that plasma free amino acid (PFAA) profiles are altered in cancer patients compared with healthy controls. A multivariate index based on PFAAs was generated from a Japanese dataset and has been previously demonstrated to be clinically valuable for discriminating patients in the early stages of lung cancer. However, it remains unclear whether similar PFAA profile changes occur in cancer patients from other populations. Therefore, this study aimed to validate the performance of this index in discriminating lung cancer patients from controls in the Korean population. METHODS Samples were collected from a total of 142 Korean subjects (72 lung cancer/70 controls) for this study. PFAAs were quantified by high-performance liquid chromatography-electrospray ionization-mass spectrometry, and the clinical performance characteristics of the amino acid multivariate index were evaluated across cancer stages and histological types. RESULTS The concentrations of several PFAAs were significantly decreased in the Korean lung cancer patients compared with the controls. Significant decreases in threonine, citrulline, histidine and tryptophan and increases in proline, isoleucine, phenylalanine and ornithine were observed, which are similar to the PFAA changes reported by a previous Japanese study. The area under the receiver-operator characteristic curve (AUC of the ROC) for the index was 0.80, and similar performances were demonstrated for the different histological types. CONCLUSIONS These results suggest that the amino acid multivariate index previously developed from a Japanese dataset has the potential to aid in the early detection of lung cancers of different histological types in Korean patients.

Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission.

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41–4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease.

Plasma amino acid profiles in healthy East Asian subpopulations living in Japan.

Profiles of plasma free amino acids (PFAAs) have been utilized as biomarkers to detect various diseases. However, few studies have investigated whether ethnicity or specific subpopulations within East Asia influence PFAA concentrations.