IL-6 facilitates cross-talk between epithelial cells and tumor- associated macrophages in Helicobacter pylori-linked gastric carcinogenesis.

PURPOSE: Helicobacter pylori (H. pylori) is a significant risk factor for development of gastric cancer (GC), one of the deadliest malignancies in the world. However, the mechanism by which H. pylori induces gastric oncogenesis remains unclear. Here, we investigated the function of IL-6 in gastric oncogenesis and macrophage-epithelial cell interactions. METHODS: We analyzed publicly available datasets to investigate the expression of IL-6 and infiltration of M2 macrophages in GC tissues, and determine the inter-cellular communication in the context of IL-6. Human gastric epithelial and macrophage cell lines (GES-1 and THP-1-derived macrophages, respectively) were used in mono- and co-culture experiments to investigate autocrine-and paracrine induction of IL-6 expression in response to H. pylori or IL-6 stimulation. RESULTS: We found that IL-6 is highly expressed in GC and modulates survival. M2 macrophage infiltration is predominant in GC and drives an IL-6 mediated communication with gastric epithelium cells. In vitro, IL-6 triggers its own expression in GES-1 and THP-1-derived macrophages cells. In addition, these cell lines are able to upregulate each other's IL-6 levels in an autocrine fashion, which is enhanced by H. pylori stimulation. CONCLUSION: This study indicates that IL-6 in the tumor microenvironment is essential for intercellular communication. We show that H. pylori enhances an IL-6-driven autocrine and paracrine positive feedback loop between macrophages and gastric epithelial cells, which may contribute to gastric carcinogenesis.

Increased Prevalence of Autoimmune Gastritis in Patients with a Gastric Precancerous Lesion.

Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal-cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset. Aim: Investigate the prevalence and characteristics of AIG in GPL patients. Methods: Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists. Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884). Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.

Methylation Mediated Silencing of miR-155 Suppresses the Development of Preeclampsia In Vitro and In Vivo by Targeting FOXO3.

Preeclampsia (PE) is a common pregnancy-related syndrome characterized by chronic immune activation. This study is aimed at exploring the role of miR-155 in the inflammatory pathogenesis of PE. Placental tissues and peripheral blood were collected from all subjects. BSP detection analysis was performed to evaluate miR-155 methylation levels. ELISA was performed to measure the levels of inflammatory cytokines and MMP2 in serum samples and cellular supernatants. HTR-8/SVneo and JEG-3 cells were transfected with miR-155 mimic and the inhibitor to establish the overexpressed miR-155 and silenced miR-155 cell models, respectively. Treatment with 5-Aza was performed to alter the DNA methylation level of miR-155. The PE rat model was established after subcutaneous injection of NG-nitro-L-arginine methyl ester. The CCK-8 assay, TUNEL staining, and Transwell assay were performed. Reverse transcription-quantitative PCR, Western blot analysis, and immunohistochemical assay were used to analyze related gene expression levels. The luciferase reporter assay was used to investigate the direct interaction between FOXO3 and miR-155. Results showed that miR-155 was remarkably upregulated and inversely correlated with the promoter methylation level in the placental tissue from PE patients. The in vitro experiments indicated that miR-155 decreased viability, migration, and invasion, but increased apoptosis in trophoblast cells. FOXO3 was confirmed as the target of miR-155. Transfection of the miR-155 inhibitor suppressed inflammation and oxidative stress, but elevated proliferation, migration, and invasion of trophoblast cells, which were abolished by 5-Aza treatment or cotransfection with si-FOXO3. In summary, our data suggested that methylation-mediated silencing of miR-155 can inhibit the apoptosis, inflammation, and oxidative stress of trophoblast cells by upregulating FOXO3.

Expression and diagnostic value of plasma protein Z and protein Z-dependent protease inhibitor in fetal growth restriction.

OBJECTIVES: Investigating the expression levels of plasma protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in fetal growth restriction (FGR) and to explore their diagnostic value in FGR. MATERIAL AND METHODS: In this study, the number of pregnant women with FGR, healthy pregnant women (Healthy Control, HC), and childbearing-age women without pregnancy (Blank Control, BC) is 79, 79, and 60, respectively; their plasma PZ and ZPI levels in each group are determined by ELISAs. Then, the correlations between these indices and FGR were assessed using Spearman analysis. Moreover, these indices' diagnostic values for FGR are evaluated using the receiver operating characteristics (ROC) curves. RESULTS: The plasma levels of PZ and ZPI are significantly decreased in the HC and FGR groups compared against the BC group (P < 0.001), whilst the levels of PZ and ZPI in the FGR groups are lower than those in the HC group (P < 0.01) notably. PZ plasma concentration has positive relationship with ZPI concentrations in the HC and FGR groups. The combination of PZ and ZPI, with the Area under the Curve (AUC) 0.92 (95% CI = 0.88-0.96), the sensitivity 0.82, and the specificity 0.88, outperforms everyone. CONCLUSIONS: Plasma PZ and ZPI are significantly decreased in pregnant women with FGR, which can be used for pregnant women's FGR screening.

An Update on Eosinophilic Esophagitis: Etiological Factors, Coexisting Diseases, and Complications.

BACKGROUND: Eosinophilic esophagitis (EoE) is an immune-mediated clinicopathological condition characterized by esophageal infiltration with eosinophils resulting in chronic inflammation and stricture. SUMMARY: The recent increase in the incidence of EoE and the characteristic presentation of symptoms with difficulty swallowing and food bolus impaction has raised key concerns of clinicians as well as researchers. EoE often presents with dysphagia, food impaction, nausea, regurgitation or vomiting, and decreased appetite. It is more common in males, affecting both adults and children. The causative manner of this condition is complex and multifactorial. Throughout recent years, researchers have made a significant contribution to understanding the pathogenesis of EoE, genetic background, natural history, work on allergy, and standardization in the evaluation of disease activity. There is relatively high prevalence of EoE among the population, emphasizing the importance of this disease. Key messages: Esophageal involvement with eosinophils may be manifested as isolated or with coexisting conditions and should be taken into consideration in the differential diagnosis. This study aimed to provide gastroenterologists with novel insights into the evaluation of esophageal involvement with eosinophils and to pay special attention to the etiological factors, coexisting clinical diseases, and complications.

The Enlargement of Abdominal Lymph Nodes Is a Characteristic of Autoimmune Liver Disease.

BACKGROUND: The enlargement of lymph nodes is a common clinical sign in connective tissue disease (CTD) and viral hepatitis. In this research, we evaluated the incidence of enlarged lymph nodes in autoimmune liver diseases (AILD). Moreover, we identified the clinical significance of abdominal lymph node enlargement in AILD. METHODS: The characteristics of abdominal lymph nodes, including their morphology and distribution, were assessed by ultrasonography and computed tomography in 125 patients with AILD, 54 with viral hepatitis, 135 with CTD, and 80 healthy controls. The pathological and laboratory results of 106 AILD patients were collected to analyze the association between lymphadenectasis and disease activity. RESULTS: Enlargement of abdominal lymph nodes was found in 69.6% of patients with AILD, 63% of patients with viral hepatitis, 29.6% of patients with CTD, and 2% of healthy controls. Alkaline phosphatase (ALP), glutamate transpeptidase (GGT), and immunoglobulin M (IgM) levels were significantly increased in AILD patients with lymphadenectasis (LA) in contrast to patients without lymphadenectasis (NLA) (P < 0.05). The pathological characteristics of inflammation, cholestasis, and focal necrosis were more common in the LA group than in the NLA group (P < 0.05). As shown by multivariate logistic regression analysis, interface hepatitis (OR = 3.651, P < 0.05), cholestasis (OR = 8.137, P < 0.05), and focal necrosis (OR = 5.212, P < 0.05) were related to LA. CONCLUSIONS: The percentage of abdominal lymph node enlargement in AILD subjects was significantly higher than that in CTD subjects. Therefore, the enlargement of lymph nodes can represent a noninvasive indicator of histological and biochemical inflammation activity in AILD.

Splenectomy Promotes Macrophage Polarization in a Mouse Model of Concanavalin A- (ConA-) Induced Liver Fibrosis.

BACKGROUND: Splenectomy can improve liver function and survival in patients with autoimmune hepatitis (AIH) and liver cirrhosis. We investigated the underlying mechanism in a mouse model of concanavalin A- (ConA-) induced liver fibrosis. METHODS: We used ConA to induce immune liver fibrosis in BALB/c mice. Splenectomy was performed alone or with the administration of dexamethasone (DEX). Changes in blood and liver tissues were evaluated. RESULTS: Mice treated with ConA for 7 weeks developed advanced liver fibrosis, while splenectomy suppressed liver fibrosis. Although the populations of macrophages/monocytes and M1 macrophages decreased after splenectomy, the inflammatory factors associated with M2 macrophages increased after splenectomy. Furthermore, the population of circulating CD11b+Ly6Chigh myeloid-derived suppressor cells (MDSCs) increased after splenectomy. After ConA treatment, elevated levels of activated and total NF-kBp65/p50 combined with DNA were observed in hepatic tissues. In contrast, the levels of NF-κB p65/p50 decreased after splenectomy. CONCLUSIONS: Splenectomy may promote the polarization of CD11b+Ly6Chigh MDSCs and the differentiation of M2 macrophages while restricting the level of NF-κB p65-p50 heterodimers. These factors may suppress the progression of liver fibrosis.