Hai-Xing Jiang

Th22 cells are associated with hepatocellular carcinoma development and progression

OBJECTIVE IL-22-producing CD4(+) T helper cells (Th22 cells) have been identified as major inducers of tissue inflammation and immune responses. Currently, no previous study explored the role of Th22 cells in the pathogenesis of hepatocellular carcinoma (HCC). The study aimed to determine the biological function of Th22 cells and its effector IL-22 in HCC patients. METHODS Forty-five HCC patients and 19 healthy controls were recruited and their peripheral blood was collected. The fresh HCC tissues, adjacent HCC tissues and ten normal liver tissues were also collected. Flow cytometry analysis was used to determine the frequencies of circulating Th22 cells and Th17 cells. Serum IL-22 levels were tested by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining and real-time polymerase chain reaction (PCR) were used to detect IL-22 protein and mRNA in tissues specimens, respectively. RESULTS Circulating Th22 cells, Th17 cells and serum IL-22 levels were significantly elevated in HCC patients compared with those of healthy controls (P<0.001). Th22 cells were showed to be positively correlated with IL-22 in HCC patients (P<0.05), but not in healthy controls. No significant differences were found in HCC patients with HBeAg positivity or negativity in term of Th22 cells and serum IL-22 levels. The expression of IL-22 protein and mRNA was highest in HCC tissues, followed by adjacent HCC tissues and normal liver tissues. Furthermore, Th22 cells, serum IL-22 levels and IL-22 mRNA were elevated at stage III-IV compared with stage I-II of HCC (P<0.05). CONCLUSIONS Elevation of circulating Th22 cells and IL-22 may be implicated in the pathogenesis of HCC, and potentially be cellular targets for therapeutic intervention.

Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines

AIM To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved. METHODS Liver fibrosis was induced in male BALB/c mice by CCl₄. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl₄-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated. RESULTS Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01). CONCLUSION The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis.

Interleukin-22 ameliorates liver fibrosis through miR-200a/beta-catenin.

IL-22 ameliorates liver fibrosis by inhibiting hepatic stellate cells (HSC), and loss of miR-200a is associated with the development of liver fibrosis. The study aimed to investigate the interplay between IL-22 and miR-200a in regulating liver fibrosis in vivo and in vitro. We observed that IL-22 significantly reduced the proliferation of HSC and increased the expression of p-STAT3. β-catenin was identified as a target gene of miR-200a by luciferase reporter assay, and upregulation of miR-200a significantly attenuated the proliferation of HSC and reduced β-catenin expression. IL-22 treatment increased expression of miR-200a and decreased expression of β-catenin in HSC. The expression of p-STAT3 and miR-200a was elevated while β-catenin was decreased in fibrotic rat liver after IL-22 treatment. Expression levels of β-catenin and p-STAT3 were inversely correlated in fibrotic rat liver and HSC. Upregulation of β-catenin suppressed expression of p-STAT3 in HSC. We concluded that IL-22 inhibits HSC activation and ameliorates liver fibrosis through enhancing expression of miR-200a and reducing expression of β-catenin, suggesting there may be a crosstalk between IL-22/STAT3 and β-catenin pathway.

Association of interleukin-10 polymorphisms with risk of irritable bowel syndrome:A meta-analysis

AIM To clarify the current understanding of the association between interleukin-10 (IL-10) polymorphisms and the risk of irritable bowel syndrome (IBS). METHODS We searched for studies in any language recorded in PubMed, Embase and Cochrane library before August 2013. The associations under allele contrast model, codominant model, dominant model, and recessive model were analyzed. The strengths of the association between IL-10 polymorphisms and IBS risk were estimated using odds ratios (OR) with 95% confidence interval (CI). Fixed effects model was used to pool the result if the test of heterogeneity was not significant, otherwise the random-effect model was selected. RESULTS Eight case-control studies analyzing three single-nucleotide polymorphisms rs1800870 (-1082 A/G), rs1800871 (-819C/T), and rs1800872 (-592A/C) of the IL-10 gene, which involved 928 cases and 1363 controls, were eligible for our analysis. The results showed that rs1800870 polymorphisms were associated with a decreased risk of IBS (GG+GA vs AA: OR = 0.80, 95%CI: 0.66-0.96), (AA+GA vs GG: OR = 0.68, 95%CI: 0.52-0.90). Subgroup analysis revealed such association only existed in Caucasian ethnicity (AA+GA vs GG, OR = 0.70, 95%CI: 0.55-0.89). The rs1800872 polymorphisms were associated with an increased risk of IBS in Asian ethnicity (CC vs GG: OR = 1.29, 95%CI: 1.01-1.16). There were no associations between rs1800871 polymorphisms and the IBS risk. CONCLUSION The results suggest that IL-10 rs1800870 confers susceptibility to the risk of IBS in Caucasian ethnicity, and the rs1800872 may associate with IBS risk in Asians. However, no significant associations are found between rs1800871 and IBS risk.

Assessment by meta-analysis of interferon-gamma for the diagnosis of tuberculous peritonitis.

AIM To investigate the performance and diagnostic accuracy of interferon-gamma (IFN-γ) for tuberculous peritonitis (TBP) by meta-analysis. METHODS A systematic search of English language studies was performed. We searched the following electronic databases: MEDLINE, EMBASE, Web of Science, BIOSIS, LILACS and the Cochrane Library. The Standards for Reporting Diagnostic Accuracy initiative and Quality Assessment for Studies of Diagnostic Accuracy tool were used to assess the methodological quality of the studies. Sensitivity, specificity, and other measures of the accuracy of IFN-γ concentration in the diagnosis of peritoneal effusion were pooled using random-effects models. Receiver operating characteristic (ROC) curves were applied to summarize overall test performance. Two reviewers independently judged study eligibility while screening the citations. RESULTS Six studies met the inclusion criteria. The average inter-rater agreement between the two reviewers for items in the quality checklist was 0.92. Analysis of IFN-γ level for TBP diagnosis yielded a summary estimate: sensitivity, 0.93 (95%CI, 0.87-0.97); specificity, 0.99 (95%CI, 0.97-1.00); positive likelihood ratio (PLR), 41.49 (95%CI, 18.80-91.55); negative likelihood ratio (NLR), 0.11 (95%CI, 0.06-0.19); and diagnostic odds ratio (DOR), 678.02 (95%CI, 209.91-2190.09). χ(2) values of the sensitivity, specificity, PLR, NLR and DOR were 5.66 (P = 0.3407), 6.37 (P = 0.2715), 1.38 (P = 0.9265), 5.46 (P = 0.3621) and 1.42 (P = 0.9220), respectively. The summary receiver ROC curve was positioned near the desirable upper left corner and the maximum joint sensitivity and specificity was 0.97. The area under the curve was 0.99. The evaluation of publication bias was not significant (P = 0.922). CONCLUSION IFN-γ may be a sensitive and specific marker for the accurate diagnosis of TBP. The level of IFN-γ may contribute to the accurate differentiation of tuberculosis (TB) ascites from non-TB ascites.

A deleterious role for Th9/IL-9 in hepatic fibrogenesis

T helper 9 (Th9) cells, a recently recognized Th cell subset, are involved in autoimmune diseases. We aimed to investigate the role of Th9/interleukin-9 (IL-9) in the pathogenesis of hepatic fibrosis. Th9 and Th17 cells were quantified in chronic hepatitis B (CHB) patients with hepatic fibrosis, HBV-associated liver cirrhosis (LC) patients and healthy controls (HC). The percentages of Th9 and Th17 cells, concentrations of IL-9 and IL-17, as well as expression of IL-17, TNF-α, IL-6, IL-4, IL-21, TGF-β1 and IFN-γ were significantly increased in plasma of CHB and LC patients compared with those in HC. Splenic Th9 and Th17 cells, plasma concentrations and liver expression of IL-9 and IL-17A were significantly elevated in mice with hepatic fibrosis compared with controls. Neutralization of IL-9 in mice ameliorated hepatic fibrosis, attenuated the activation of hepatic stellate cells, reduced frequencies of Th9, Th17 and Th1 cells in spleen, and suppressed expression of IL-9, IL-17A, IFN-γ, TGF-β1, IL-6, IL-4 and TNF-α in plasma and liver respectively. Our data suggest a deleterious role of Th9/IL-9 in increasing hepatic fibrosis and exacerbating disease endpoints, indicating that Th9/IL9 based immunotherapy may be a promising approach for treating hepatic fibrosis.

Carbohydrate antigen 19-9 for differential diagnosis of pancreatic carcinoma and chronic pancreatitis.

AIM To evaluate the utility of carbohydrate antigen 19-9 (CA19-9) for differential diagnosis of pancreatic carcinoma and chronic pancreatitis. METHODS We searched the literature for studies reporting the sensitivity, specificity, and other accuracy measures of serum CA19-9 levels for differentiating pancreatic carcinoma and chronic pancreatitis. Pooled analysis was performed using random-effects models, and receiver operating characteristic (ROC) curves were generated. Study quality was assessed using Standards for Reporting Diagnostic Accuracy and Quality Assessment for Studies of Diagnostic Accuracy tools. RESULTS A total of 34 studies involving 3125 patients with pancreatic carcinoma and 2061 patients with chronic pancreatitis were included. Pooled analysis of the ability of CA19-9 level to differentiate pancreatic carcinoma and chronic pancreatitis showed the following effect estimates: sensitivity, 0.81 (95%CI: 0.80-0.83); specificity, 0.81 (95%CI: 0.79-0.82); positive likelihood ratio, 4.08 (95%CI: 3.39-4.91); negative likelihood ratio, 0.24 (95%CI: 0.21-0.28); and diagnostic odds ratio, 19.31 (95%CI: 14.40-25.90). The area under the ROC curve was 0.88. No significant publication bias was detected. CONCLUSION Elevated CA19-9 by itself is insufficient for differentiating pancreatic carcinoma and chronic pancreatitis, however, it increases suspicion of pancreatic carcinoma and may complement other clinical findings to improve diagnostic accuracy.

Association of interleukin 22 polymorphisms with gastric cancer risk

Interleukin (IL)-22 has been implicated in inflammation and tumorigenesis. To date, no studies have investigated the role of IL-22 polymorphism in the carcinogenesis of gastric cancer (GC). In this study, we aimed to investigate the association of IL-22 polymorphisms with the risk of GC in a Chinese population. One hundred eight GC patients and 110 healthy controls were included in the study. IL-22 rs1179251, rs2227485, and rs2227473 polymorphisms were determined by PCR amplification and DNA sequencing. Haplotypes were constructed, and a possible association of these haplotypes with GC was assessed. The distribution of IL-22 rs1179251 polymorphism with clinical parameters was also analyzed. The IL-22 rs1179251 polymorphism was significantly associated with an increased risk of GC (p < 0.05). Stratified analysis revealed that rs1179251 was associated with advanced stages, lymph node metastases, and distant metastases of GC (p < 0.05). No associations were found between rs2227485 and rs2227473 and the risk of GC (p > 0.05). Three possible haplotypes (Crs1179251-Crs2227485-Grs2227485, Crs1179251-Trs2227485-Grs2227485, and Grs1179251-Trs2227485-Ars2227485) were identified, but no associations were found between these and the risk of GC (p > 0.05). In summary, our study demonstrates that the rs1179251 polymorphism of IL-22 was associated with an increased risk of GC and may influence the progression of GC. Future larger studies with other ethnic populations are required to confirm these findings.

Meta-analysis of prognostic and clinical significance of CD44v6 in esophageal cancer

Abstract CD44v6 is a cell adhesion molecule that plays an important role in the development and progression of esophageal cancer. However, the prognostic value and clinical significance of CD44v6 in esophageal cancer remains controversial. In the present study, we aimed to clarify these relationships through a meta-analysis. We performed a comprehensive search of studies from PubMed, EMBASE, Ovid library database, Google scholar, and Chinese National Knowledge Infrastructure databases that were published before June 2015. The odds ratio (OR) and pooled hazard ratio (HR) with the 95% confidence intervals (CI) were used to estimate the effects. Twenty-one studies including 1504 patients with esophageal cancer were selected to assess the prognostic value and clinical significance of CD44v6 in these patients. The results showed that the expression of CD44v6 was higher in esophageal cancer tissue than in normal colorectal tissue (OR = 9.19, 95% CI = 6.30–13.42). Moreover, expression of CD44v6 was higher in patients with lymphoid nodal metastasis, compared to those without (OR = 6.91, 95% CI = 4.81–9.93). The pooled results showed that CD44v6 was associated with survival in patients with esophageal cancer (HR = 2.47, 95% CI = 1.56–3.92). No significant difference in CD44v6 expression was found in patients with different histological types and tumor stages (both P > 0.05). Moreover, no publication bias was found among the studies (all P > 0.05). This meta-analysis demonstrates that CD44v6 is associated with the metastasis of esophageal cancer and a poor prognosis, but is not associated with the histological types and tumor stages.

Inhibition of hepatic stellate cell proliferation by bone marrow mesenchymal stem cells via regulation of the cell cycle in rat.

The present study aimed to observe the effect of rat bone marrow mesenchymal stem cells (MSCs) in vitro on hepatic stellate cell (HSC) RhoA signaling factors and the expression of the cell cycle regulators P27 and cyclin D1. Rat HSC-T6 and fibroblast cells were divided into control, negative control and MSC experimental groups. The cell proliferation rate was examined using the WST8 assay. The cell cycle was analyzed using flow cytometry. RT-PCR and western blot analysis were used to examine cyclin in D1 (cyclin D1), RhoA and P27 mRNA and protein expression in HSCs. After 12 h of co-culture, transition of the MSCs from the G0/G1 to S phase was blocked by HSCs. In the MSC experimental group, the RhoA mRNA and RhoA protein expression showed a decreasing trend with time, which was statistically significant compared with that in the control and negative control groups. MSC P27 protein expression showed an increasing trend with time. RhoA and P27 expression were significantly negatively correlated. After 24 h of co-culture, MSCs inhibited cyclin D1 expression. The difference was statistically significant in the experimental and control groups as well as in the negative control group (P<0.01). In conclusion, co-culture of HSCs with MSCs is capable of inhibiting HSC proliferation, promoting apoptosis and inhibiting RhoA expression. Reduced RhoA activity may induce an upregulation in P27 protein expression in HSCs, which promotes the inhibition of cyclin D1 by MSCs and induces cell cycle arrest at the G0/G1 phase, indicating a role in inhibiting rat HSC proliferation.