IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma

Background We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC).Methods The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies.Results We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25–3 p axis. Monocytes and TAMs showed significantly increased miR-25–3 p expression, which could target the 3′ untranslated region of PTPRO. The miR-25–3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25–3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25–3 p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in an orthotopic tumor transplantation model.Conclusions Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25–3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling

Impacts of Haze on Housing Prices: An Empirical Analysis Based on Data from Chengdu (China)

Based on cross-section data of 20 districts in Chengdu, this article reviews the relationships between haze and housing prices with the combined application of Spatial Error Model (SEM) and Spatial Lag Model (SLM). The results illustrate that haze significantly have negative impacts on both the selling and rental prices of houses. Controlling other variables, if the air quality index rises by 0.1, the housing selling prices and rental prices will drop by 3.97% and 4.01%, respectively. Interestingly, housing rental prices have a more significant response to the air quality than housing sale prices. Residents are willing to pay a premium for better air quality and the influence of air quality is partially reflected in housing prices, which indicates that better air quality has been becoming a scarce resource with the improvement of people’s living standard. Furthermore, the impacts of haze on housing prices are also expected to lead to a “crowding out effect” in different regions. This would be detrimental for human capital accumulation and will accelerate the regional divergence in the internal economy and population structure, thus forming a region “fence” within cities

Hepatic haemangiomas: possible association with IL-17

ABSTRACT has been cast as a major player in angiopoiesis of carcinoma, but its role in hepatic haemangioma is not entirely clear. Aim The aim of this study is to address the expression levels and the molecular mechanism underlying the role of IL-17 on hepatic haemangioma progression. Methods and Results 20 hepatic haemangioma patients and 15 healthy subjects were included in this study. IL-17 mRNA levels were examined by PCR-based methods and protein levels by western blot. We observed a significant increase in tissue IL-17 mRNA and protein levels in hepatic haemangioma compared to normal liver tissue. Matrix metalloproteinase protein levels were slightly elevated in haemangiomas compared to normal, and IL-6 and phospho-stat3 levels were markedly elevated. However, no differences in mRNA levels of angiogenesis-associated cytokines such as vascular endothelial growth factor were seen in hepatic haemangiomas compared to normal cases taken from donor livers at the time of organ harvest. IL-17 was localised to CD4-positive cells by flow cytometry and to stromal cells and endothelial cells by immunohistochemistry. Owing to the absence of an animal model of haemangioma, we examined the effects of IL-17 on angiogenesis-related functions of vascular endothelial cells in vitro. Notably, IL-17, when added to cell cultures of human umbilical cord-derived endothelial cells, had an effect on the secretion of IL-6 and p-stat3. Conclusions Based on these findings, we propose that IL-17 may mediate the angiogenesis in a IL-6-Stat3-dependent manner and play an important role in the pathophysiology of hepatic haemangioma

HULC and Linc00152 Act as Novel Biomarkers in Predicting Diagnosis of Hepatocellular Carcinoma

Background/Aims: The alterations of long non-coding RNAs (lncRNAs) are related to multiple diseases. They can be detected in plasma as biomarkers for the diagnosis of multiple diseases. In this study, we aimed to determine the expression of circulating lncRNAs in human, which may be promising biomarkers for the diagnosis of hepatocellular carcinoma (HCC). Methods: Eight lncRNAs were chosen as candidates on the basis of the literature to evaluate the diagnostic value and accuracy of the plasma lncRNA profiling system. The candidate lncRNAs were validated by qRT-PCR arranged in the training and validation sets. Additional double-blind testing was performed in 20 patients clinically suspected of having HCC. Results: Circulating HULC and Linc00152 were significantly up-regulated in plasma samples of HCC patients during training set and validation set. Areas under the receiver operating characteristic (ROC) curves of the validated two lncRNAs signature were 0.78 and 0.85, respectively. Combination of HULC and Linc00152 possessed a moderate ability to discrimination between HCC and control with an area under ROC value of 0.87 while the combination of AFP was 0.89 with a positive correlation with tissues expression. Conclusions: Our results suggest that both plasma levels of HULC and Linc00152 achieve a fine diagnostic accuracy in diagnosing ontogenesis and metastasis of HCC and may act as novel biomarkers for HCC

Aggravated Liver Injury but Attenuated Inflammation in PTPRO-Deficient Mice Following LPS/D-GaIN Induced Fulminant Hepatitis

Background/Aims: Critical roles of PTPRO and TLR4 have been implicated in hepatocellular carcinoma. However, little is known about their modifying effects on inflammation-related diseases in liver, particularly fulminant hepatitis (FH). We aim to investigate the potential role of PTPRO and its interaction with TLR4 in LPS/D-GaIN induced FH. Methods: A LPS/D-GaIN induced mouse FH model was used. RAW264.7 cells were transfected with PTPRO over-expressed lentiviral plasmids for further investigation. Results: The mortality of PTPRO KO mice is higher than WT mice after LPS/D-GaIN administration. Aggravated liver injury was demonstrated by increased level of serous ALT and AST and numerous hepatic cells death in PTPRO KO mice following LPS/D-GaIN administration. Interestingly, inflammation was attenuated in PTPRO-deficient mice following LPS/D-GaIN administration, which was suggested by decreased inflammatory cytokines (TNF-a, IFN-γ, IL-1ß, IL-6, IL-17A and IL-12) and cells infiltrating into spleen (CD3+IFN-γ+ cells, CD3+TNF-a+ cells, F4/80+/TLR4+ cells). A feedback regulation between PTPRO and TLR4 dependent on NF-γB signaling pathway was demonstrated in vivo and in vitro. Conclusion: PTPRO plays an important role in FH by interacting with TLR4. The crosstalk between PTPRO and TLR4 is a novel bridge linking innate immune and adaptive immune in acute liver injury

Evaluation of Epstein-Barr Virus Latent Membrane Protein 2 Specific T-Cell Receptors Driven by T-Cell Specific Promoters Using Lentiviral Vector

Transduction of latent membrane protein 2 (LMP2)-specific T-cell receptors into activated T lymphocytes may provide a universal, MHC-restricted mean to treat EBV-associated tumors in adoptive immunotherapy. We compared TCR-specific promoters of distinct origin in lentiviral vectors, that is, Vβ6.7, delta, luria, and Vβ5.1 to evaluate TCR gene expression in human primary peripheral blood monocytes and T cell line HSB2. Vectors containing Vβ 6.7 promoter were found to be optimal for expression in PBMCs, and they maintained expression of the transduced TCRs for up to 7 weeks. These cells had the potential to recognize subdominant EBV latency antigens as measured by cytotoxicity and IFN-γ secretion. The nude mice also exhibited significant resistance to the HLA-A2 and LMP2-positive CNE tumor cell challenge after being infused with lentiviral transduced CTLs. In conclusion, LMP2-specific CTLs by lentiviral transduction have the potential use for treatment of EBV-related tumors