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Articles by J Xu
Total Records ( 18 ) for J Xu
  J Xu , S Stanislaus , N Chinookoswong , Y. Y Lau , T Hager , J Patel , H Ge , J Weiszmann , S. C Lu , M Graham , J Busby , R Hecht , Y. S Li , Y Li , R Lindberg and M. M. Veniant

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40–60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.

  J Xu , K Gupta , W. V Stoecker , Y Krishnamurthy , H. S Rabinovitz , A Bangert , D Calcara , M Oliviero , J. M Malters , R Drugge , R. J Stanley , R. H Moss and M. E. Celebi

Objective  To identify and analyze subtypes of globules based on size, shape, network connectedness, pigmentation, and distribution to determine which globule types and globule distributions are most frequently associated with a diagnosis of malignant melanoma.

Design  Retrospective case series of dermoscopy images with globules.

Setting  Private dermatology practices.

Participants  Patients in dermatology practices.

Intervention  Observation only.

Main Outcome Measure  Association of globule types with malignant melanoma.

Results  The presence of large globules (odds ratio [OR], 5.25) and globules varying in size (4.72) or shape (5.37) had the highest ORs for malignant melanoma among all globule types and combinations studied. Classical globules (dark, discrete, convex, and 0.10-0.20 mm) had a higher risk (OR, 4.20) than irregularly shaped globules (dark, discrete, and not generally convex) (2.89). Globules connected to other structures were not significant in the diagnosis of malignant melanoma. Of the different configurations studied, asymmetric clusters have the highest risk (OR, 3.02).

Conclusions  The presence of globules of varying size or shape seems to be more associated with a diagnosis of malignant melanoma than any other globule type or distribution in this study. Large globules are of particular importance in the diagnosis of malignant melanoma.

  R. J Klein , C Hallden , A. M Cronin , A Ploner , F Wiklund , A. S Bjartell , P Stattin , J Xu , P. T Scardino , K Offit , A. J Vickers , H Gronberg and H. Lilja

Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding β-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings. Cancer Prev Res; 3(5); 611–9. ©2010 AACR.

  J Xu , M Futakuchi , M Iigo , K Fukamachi , D. B Alexander , H Shimizu , Y Sakai , S Tamano , F Furukawa , T Uchino , H Tokunaga , T Nishimura , A Hirose , J Kanno and H. Tsuda

Titanium dioxide (TiO2) is evaluated by World Health Organization/International Agency for Research on Cancer as a Group 2B carcinogen. The present study was conducted to detect carcinogenic activity of nanoscale TiO2 administered by a novel intrapulmonary spraying (IPS)-initiation–promotion protocol in the rat lung. Female human c-Ha-ras proto-oncogene transgenic rat (Hras128) transgenic rats were treated first with N-nitrosobis(2-hydroxypropyl)amine (DHPN) in the drinking water and then with TiO2 (rutile type, mean diameter 20 nm, without coating) by IPS. TiO2 treatment significantly increased the multiplicity of DHPN-induced alveolar cell hyperplasias and adenomas in the lung, and the multiplicity of mammary adenocarcinomas, confirming the effectiveness of the IPS-initiation–promotion protocol. TiO2 aggregates were localized exclusively in alveolar macrophages and had a mean diameter of 107.4 nm. To investigate the underlying mechanism of its carcinogenic effects, TiO2 was administered to wild-type rats by IPS five times over 9 days. TiO2 treatment significantly increased 8-hydroxydeoxy guanosine level, superoxide dismutase activity and macrophage inflammatory protein 1 (MIP1) expression in the lung. MIP1, detected in the cytoplasm of TiO2-laden alveolar macrophages in vivo and in the media of rat primary alveolar macrophages treated with TiO2 in vitro, enhanced proliferation of human lung cancer cells. Furthermore, MIP1, also detected in the sera and mammary adenocarcinomas of TiO2-treated Hras128 rats, enhanced proliferation of rat mammary carcinoma cells. These data indicate that secreted MIP1 from TiO2-laden alveolar macrophages can cause cell proliferation in the alveoli and mammary gland and suggest that TiO2 tumor promotion is mediated by MIP1 acting locally in the alveoli and distantly in the mammary gland after transport via the circulation.

  J Xu , F. A Ismat , T Wang , M. M Lu , N Antonucci and J. A. Epstein

Rationale: Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, and characteristic cutaneous findings. NF1 patients also have an increased incidence of cardiovascular diseases, including obstructive vascular disorders and hypertension. The disease gene, NF1, encodes neurofibromin, a ubiquitously expressed protein that acts, in part, as a Ras-GAP (GTP-ase activating protein), downregulating the activity of activated Ras protooncogenes. In animal models, endothelial and smooth muscle expression of the disease gene is critical for normal heart development and the prevention of vascular disease, respectively.

Objective: To determine the role of NF1 in the postnatal and adult heart.

Methods and Results: We generated mice with homozygous loss of the murine homolog Nf1 in myocardium (Nf1mKO) and evaluated their hearts for biochemical, structural, and functional changes. Nf1mKO mice have normal embryonic cardiovascular development but have marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis in the adult. Hyperactivation of Ras and downstream pathways are seen in the heart with the loss of Nf1, along with activation of a fetal gene program.

Conclusions: This report describes a critical role of Nf1 in the regulation of cardiac growth and function. Activation of pathways known to be involved in cardiac hypertrophy and dysfunction are seen with the loss of myocardial neurofibromin.

  H Massaeli , J Guo , J Xu and S. Zhang

Rationale: The human ether-a-go-go–related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier potassium channel (IKr) that is important for cardiac repolarization. Dysfunction of HERG causes long QT syndrome (LQTS) which can lead to sudden cardiac death. We previously showed that a reduction in extracellular K+ concentration ([K+]o) prolongs QT intervals in intact rabbits, and decreases the cell surface density of IKr in rabbit ventricular myocytes and of the HERG channel expressed in human embryonic kidney (HEK) cells.

Objective: The goal of the present study was to gain insights into the mechanisms for low [K+]o induced reduction in HERG expression levels.

Methods and Results: Using patch clamp, Western blot and confocal imaging methods, we demonstrated that at low [K+]o, the HERG channel entered a novel nonconducting state. Furthermore, this novel functional state triggered rapid internalization and degradation of the cell surface HERG channels. Thus, our data demonstrated for the first time a direct link between a gating state and the plasma membrane stability of an ion channel, HERG. Using HERG-permeant cations and site-directed mutagenesis, we identified the sites in the channel which are involved in the K+o dependence of HERG channels.

Conclusions: Extracellular K+ is a prerequisite for HERG function and membrane stability.

  S Wang , M Zhang , B Liang , J Xu , Z Xie , C Liu , B Viollet , D Yan and M. H. Zou

Rational: AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established.

Objective: The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function.

Methods and Results: The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91phox, p47phox, p67phox, NOX1 to -4), NAD(P)H oxidase–mediated superoxide production, 26S proteasome activity, IB degradation, and nuclear translocation of nuclear factor (NF)-B (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPK2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPK2–/– mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPK2–/– mice. Analysis of aortic endothelial cells from AMPK2–/– mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPK2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91phox, p47phox, p67phox, NOX1 and -4), NAD(P)H oxidase–mediated superoxide production, 26S proteasome activity, IB degradation, and nuclear translocation of NF-B (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPK2 in low-density lipoprotein receptor knockout (LDLr–/–) strain markedly increased 26S proteasome activity, IB degradation, NF-B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor.

Conclusions: We conclude that AMPK2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells.

  E Lacson , J Xu , S. F Lin , S. G Dean , J. M Lazarus and R. M. Hakim

Background and objectives: The Short Form 12 (SF-12) has not been validated for long-term dialysis patients. The study compared physical and mental component summary (PCS/MCS) scores from the SF-36 with those from the embedded SF-12 in a national cohort of dialysis patients.

Design, setting, participants, & measurements: All 44,395 patients who had scorable SF-36 and SF-12 from January 1, 2006, to December 31, 2006, and were treated at Fresenius Medical Care, North America facilities were included. Death and first hospitalization were followed for up to 1 year from the date of survey. Correlation and agreement were obtained between PCS-36 and PCS-12 and MCS-36 and MCS-12; then Cox models were constructed to compare associated hazard ratios (HRs) between them.

Results: Physical and mental dimensions both exhibited excellent intraclass correlation coefficients of 0.94. Each incremental point for both PCS-12 and PCS-36 was associated with a 2.4% lower adjusted HR of death and 0.4% decline in HR for first hospitalization (both P < 0.0001). Corresponding improvement in HR of death for each MCS point was 1.2% for MCS-12 and 1.3% for MCS-36, whereas both had similar 0.6% lower HR for hospitalization per point (all P < 0.0001).

Conclusions: The use of the SF-12 alone or as part of a larger survey is valid in dialysis patients. Composite scores from the SF-12 and SF-36 have similar prognostic association with death and hospitalization risk. Prospective longitudinal studies of SF-12 surveys that consider responsiveness to specific clinical, situational, and interventional changes are needed in this population.

  W Zhang , L Wang , Y Liu , J Xu , G Zhu , H Cang , X Li , M Bartlam , K Hensley , G Li , Z Rao and X. C. Zhang

Eukaryotic lanthionine synthetase C-like protein 1 (LanCL1) is homologous to prokaryotic lanthionine cyclases, yet its biochemical functions remain elusive. We report the crystal structures of human LanCL1, both free of and complexed with glutathione, revealing glutathione binding to a zinc ion at the putative active site formed by conserved GxxG motifs. We also demonstrate by in vitro affinity analysis that LanCL1 binds specifically to the SH3 domain of a signaling protein, Eps8. Importantly, expression of LanCL1 mutants defective in Eps8 interaction inhibits nerve growth factor (NGF)-induced neurite outgrowth, providing evidence for the biological significance of this novel interaction in cellular signaling and differentiation.

  J Xu , J. A Watts , S. D Pope , P Gadue , M Kamps , K Plath , K. S Zaret and S. T. Smale

We reported previously that well-characterized enhancers but not promoters for typical tissue-specific genes, including the classic Alb1 gene, contain unmethylated CpG dinucleotides and evidence of pioneer factor interactions in embryonic stem (ES) cells. These properties, which are distinct from the bivalent histone modification domains that characterize the promoters of genes involved in developmental decisions, raise the possibility that genes expressed only in differentiated cells may need to be marked at the pluripotent stage. Here, we demonstrate that the forkhead family member FoxD3 is essential for the unmethylated mark observed at the Alb1 enhancer in ES cells, with FoxA1 replacing FoxD3 following differentiation into endoderm. Up-regulation of FoxD3 and loss of CpG methylation at the Alb1 enhancer accompanied the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. Studies of two genes expressed in specific hematopoietic lineages revealed that the establishment of enhancer marks in ES cells and iPS cells can be regulated both positively and negatively. Furthermore, the absence of a pre-established mark consistently resulted in resistance to transcriptional activation in the repressive chromatin environment that characterizes differentiated cells. These results support the hypothesis that pluripotency and successful reprogramming may be critically dependent on the marking of enhancers for many or all tissue-specific genes.

  J Xu , V. G Sankaran , M Ni , T. F Menne , R. V Puram , W Kim and S. H. Orkin

The developmental switch from human fetal () to adult (β) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of -globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human β-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)–chip analysis. BCL11A binds the upstream locus control region (LCR), -globin, and the intergenic regions between -globin and -globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the β-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human β-globin cluster along with GATA1, and cooperate in silencing -globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of -globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the β-globin locus.

  X Lu , J. A Shapiro , C. T Ting , Y Li , C Li , J Xu , H Huang , Y. J Cheng , A. J Greenberg , S. H Li , M. L Wu , Y Shen and C. I. Wu

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

  N Chen , W Wang , Y Huang , P Shen , D Pei , H Yu , H Shi , Q Zhang , J Xu , Y Lv and Q. Fan

Background. The study was performed to investigate the prevalence, awareness and the risk factors of chronic kidney disease (CKD) in the community population in Shanghai, China.

Methods. A total of 2596 residents were randomly recruited from the community population in Shanghai, China. All were screened for albuminuria, haematuria, morning spot urine albumin-to-creatinine ratio and renal function. Serum creatinine, uric acid, cholesterol, triglyceride and haemoglobin were assessed. A simplified MDRD equation was used to estimate the glomerular filtration rate (eGFR). All studied subjects were screened by kidney ultrasound. Haematuria, if present in the morning spot urine dipstick test, was confirmed by microscopy. The associations among the demographic characteristics, health characteristics and indicators of kidney damage were examined.

Results. Two thousand five hundred and fifty-four residents (n = 2554), after giving informed consent and with complete data, were entered into this study. Albuminuria and haematuria were detected in 6.3% and 1.2% of all the studied subjects, respectively, whereas decreased kidney function was found in 5.8% of all studied subjects. Approximately 11.8% of subjects had at least one indicator of kidney damage. The rate of awareness of CKD was 8.2%. The logistic regression model showed that age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis each contributed to the development of CKD.

Conclusion. This is the first Shanghai community-based epidemiological study data on Chinese CKD patients. The prevalence of CKD in the community population in Shanghai is 11.8%, and the rate of awareness of CKD is 8.2%. All the factors including age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis are positively correlated with the development of CKD in our studied subjects.

  J Xu , A. T De Jong , G Chen , H. K Chow , C. O Damaso , A Schwartz Mittelman and J. A. Shin

To explore the role of the HLH subdomain in bHLHZ proteins, we designed sets of minimalist proteins based on bHLHZ protein Max, bHLH/PAS protein Arnt and bZIP protein C/EBP. In the first, the Max bHLH and C/EBP leucine zipper were fused such that the leucine heptad repeats were not in register; therefore, the protein dimerization interface was disrupted. Max1bHLH-C/EBP showed little ability to activate transcription from the E-box (5'-CACGTG) in the yeast one-hybrid assay, and no E-box binding by quantitative fluorescence anisotropy. Max1bHLH-C/EBP's activity was significantly improved after library selection (three amino acids randomized between HLH and leucine zipper), despite the Max bHLH and C/EBP zipper still being out of register: a representative mutant gave a high nanomolar Kd value for E-box binding. Thus, selection proved to be a powerful tool for salvaging the flawed Max1bHLH-C/EBP, although the out-of-register mutants still did not achieve the strong DNA-binding affinities displayed by their in-register counterparts. ArntbHLH-C/EBP hybrids further demonstrated the importance of maintaining register, as out-of-register mutants showed no E-box-responsive activity, whereas the in-register hybrid showed moderate activity. In another design, we eliminated the HLH altogether and fused the Max basic region to the C/EBP zipper to generate bZIP-like hybrids. Despite numerous designs and selections, these hybrids possessed no E-box-responsive activity. Finally, we tested the importance of the loop sequence in MaxbHLHZ by fluorescence and circular dichroism. In one mutant, the loop was shortened by two residues; in the other, the Lys57:DNA-backbone interaction was abolished by mutation to Gly57. Both showed markedly decreased E-box-binding relative to MaxbHLHZ. Our results suggest that, in contrast to the more rigid bZIP, the HLH is capable of significant conformational adaptation to enable gene-regulatory function and is required for protein dimerization and positioning the basic region for DNA recognition.

  H Amlal , S Petrovic , J Xu , Z Wang , X Sun , S Barone and M. Soleimani

The anion exchanger Pendrin, which is encoded by SLC26A4 (human)/Slc26a4 (mouse) gene, is localized on the apical membrane of non-acid-secreting intercalated (IC) cells in the kidney cortical collecting duct (CCD). To examine its role in the mediation of bicarbonate secretion in vivo and the apical Cl/HCO3 exchanger in the kidney CCD, mice with genetic deletion of pendrin were generated. The mutant mice show the complete absence of pendrin expression in their kidneys as assessed by Northern blot hybridization, Western blot, and immunofluorescence labeling. Pendrin knockout (KO) mice display significantly acidic urine at baseline [pH 5.20 in KO vs. 6.01 in wild type (WT); P < 0.0001] along with elevated serum HCO3 concentration (27.4 vs. 24 meq/l in KO vs. WT, respectively; P < 0.02), consistent with decreased bicarbonate secretion in vivo. The urine chloride excretion was comparable in WT and KO mice. For functional studies, CCDs were microperfused and IC cells were identified by their ability to trap the pH fluorescent dye BCECF. The apical Cl/HCO3 exchanger activity in B-IC and non-A, non-B-IC cells, as assessed by intracellular pH monitoring, was significantly reduced in pendrin-null mice. The basolateral Cl/HCO3 exchanger activity in A-IC cells and in non-A, non-B-IC cells, was not different in pendrin KO mice relative to WT animals. Urine NH4+ (ammonium) excretion increased significantly, consistent with increased trapping of NH3 in the collecting duct in pendrin KO mice. We conclude that Slc26a4 (pendrin) deletion impairs the secretion of bicarbonate in vivo and reduces apical Cl/HCO3 exchanger activity in B-IC and non-A, non-B-IC cells in CCD. Additional apical Cl/HCO3 exchanger(s) is (are) present in the CCD.

  M. A Esteban , J Xu , J Yang , M Peng , D Qin , W Li , Z Jiang , J Chen , K Deng , M Zhong , J Cai , L Lai and D. Pei

Induced pluripotent stem cell (iPS) technology appears to be a general strategy to generate pluripotent stem cells from any given mammalian species. So far, iPS cells have been reported for mouse, human, rat, and monkey. These four species have also established embryonic stem cell (ESC) lines that serve as the gold standard for pluripotency comparisons. Attempts have been made to generate porcine ESC by various means without success. Here we report the successful generation of pluripotent stem cells from fibroblasts isolated from the Tibetan miniature pig using a modified iPS protocol. The resulting iPS cell lines more closely resemble human ESC than cells from other species, have normal karyotype, stain positive for alkaline phosphatase, express high levels of ESC-like markers (Nanog, Rex1, Lin28, and SSEA4), and can differentiate into teratomas composed of the three germ layers. Because porcine physiology closely resembles human, the iPS cells reported here provide an attractive model to study certain human diseases or assess therapeutic applications of iPS in a large animal model.

  D. M Kuang , Q Zhao , C Peng , J Xu , J. P Zhang , C Wu and L. Zheng

Macrophages (M) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of M to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/M in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/M may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.

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