angiogenin and Inflammation

Antimicrobial peptides are effector molecules of innate immunity with microbicidal and pro- or anti-inflammatory activities. Their role is now widening following evidence that one such multifunctional peptide, LL-37, induces angiogenesis, a process essential for host defense, wound healing, and tissue repair.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antimicrobial Cationic Peptides; Cathelicidins; Humans; Inflammation; Models, Biological; Neovascularization, Pathologic; Peptides; Prodrugs; Ribonuclease, Pancreatic

Paternal environmental inputs can influence various phenotypes in offspring, presenting tremendous implications for basic biology and public health and policy. However, which signals function as a nexus to transmit paternal environmental inputs to offspring remains unclear. Here we show that offspring of fathers with inflammation exhibit metabolic disorders including glucose intolerance and obesity. Deletion of a mouse tRNA RNase, Angiogenin (Ang), abolished paternal inflammation-induced metabolic disorders in offspring. Additionally, Ang deletion prevented the inflammation-induced alteration of 5'-tRNA-derived small RNAs (5'-tsRNAs) expression profile in sperm, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Microinjection of sperm 30-40 nt RNA fractions (predominantly 5'-tsRNAs) from inflammatory Ang

Topics: Animals; Epigenesis, Genetic; Inflammation; Lipopolysaccharides; Male; Metabolic Syndrome; Mice; Mutation; Paternal Exposure; Phenotype; Ribonuclease, Pancreatic; RNA, Small Untranslated; RNA, Transfer; Spermatozoa

Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time.. In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated.. Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01).. In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.

Topics: Angiography; Area Under Curve; Follow-Up Studies; Humans; Hypertension, Portal; Inflammation; Leukocyte Count; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Ribonuclease, Pancreatic; ROC Curve; Vena Cava, Inferior

Angiogenin (ANG) is involved in the innate immune system and inflammatory disease. The aim of this study is to evaluate the anti-inflammatory effects of ANG in an endotoxin induced uveitis (EIU) rat model and the pathways involved. EIU rats were treated with balanced salt solution (BSS), a non-functional mutant ANG (mANG), or wild-type ANG (ANG). The integrity of the blood-aqueous barrier was evaluated by the infiltrating cell and protein concentrations in aqueous humor. Histopathology, Western blot, and real-time qRT-PCR of aqueous humor and ocular tissue were performed to analyze inflammatory cytokines and transcription factors. EIU treated with ANG had decreased inflammatory cells and protein concentrations in the anterior chamber. Compared to BSS and mANG, ANG treatment showed reduced expression of IL-1β, IL-8, TNF-α, and Myd88, while the expression of IL-4 and IL-10 was increased. Western blot of ANG treatment showed decreased expression of IL-6, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and phosphorylated NF-κB and increased expression of IL-10. In conclusion, ANG seems to reduce effectively immune mediated inflammation in the EIU rat model by reducing the expression of proinflammatory cytokines, while increasing the expression of anti-inflammatory cytokines through pathways related to NF-κB. Therefore, ANG shows potential for effectively suppressing immune-inflammatory responses in vivo.

Topics: Animals; Anti-Inflammatory Agents; Cell Nucleus; Cytokines; Endotoxins; Inflammation; Inflammation Mediators; Male; Models, Biological; Myeloid Differentiation Factor 88; NF-kappa B; Protein Transport; Rats, Sprague-Dawley; Ribonuclease, Pancreatic; RNA, Messenger; Toll-Like Receptor 4; Uveitis

Blood coagulation is one of the most important host-defending mechanisms in vivo by maintaining the blood pressure after injury. However, besides maintaining homeostasis, blood coagulation and the contributing factors are directly linked to pathological conditions, such as thromboembolism and inflammation, leading to cardiovascular diseases, among others. As anti-inflammatory drugs may reduce cardiovascular events, we hypothesized in this study that the direct thrombin inhibitor dabigatran may reduce cytokine, growth factor and chemokine expression in vitro.. Initially, human whole blood was incubated in tubes for serum, EDTA plasma, and heparinized plasma. Furthermore, human PBMCs were isolated and incubated under different culture conditions, including the treatment with human serum or thrombin, respectively. The effect of the oral anticoagulant dabigatran on pro-inflammatory cytokines, growth factors and chemokines was investigated by ELISA.. Conditioned serum resulted in a significant alteration of the secretome's protein levels after 24 h. However, solely ANG showed a dose-dependent increment by the addition of serum (79.8 ± 9.2 ng/mL) in comparison to baseline (0.2 ± 0.2 ng/mL), as it was in trend for thrombin treatment. Furthermore, the pre-treatment of PBMCs with different doses of dabigatran significantly lowered supernatant protein levels measured. Moreover, dabigatran was shown to decrease most notably the growth factor and chemokine levels in the PBMC's secretome that were treated with 200 ng/mL thrombin in a dose-dependent manner.. In conclusion, novel oral anticoagulants, such as dabigatran, could help to reduce not only procoagulatory effects in inflammatory conditions but could also reduce proinflammatory stimuli via reduced expression of cytokines and chemokines.

Topics: Adult; Antithrombins; Blood Coagulation; Cells, Cultured; Chemokines; Cytokines; Dabigatran; Dose-Response Relationship, Drug; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Leukocytes, Mononuclear; Ribonuclease, Pancreatic

Biocompatibility of hemodialysis (HD) systems have been considerably improved. However, mortality and morbidity rates of patients have remained high, raising questions regarding the biocompatibility of current systems. In the present study, 70 patients on regular HD (51 males; mean age, 63 years; median duration of HD, 18 months) with high-performance membrane (polysulfone, 77%; polymethylmethacrylate, 23%) at Tohoku University Hospital were examined. Blood samples before and after HD, were subjected to measure apoptosis cells of white blood cells, plasma levels of the following molecules: myeloperoxidase (MPO), pentraxin 3 (PTX3), angiogenin, complements, and 17 cytokines. The main findings were as follows: significant decreases in leukocyte counts by dialysis, significant increases in apoptosis-positive leukocytes by dialysis (neutrophils and monocytes), and significant decrease in plasma angiogenin accompanying increase in plasma MPO and PTX3 levels, with no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products by dialysis. The findings underlined the unsolved issue of bio-incompatibility of HD systems, and suggest the possible pathology of neutrophil apoptosis accompanying MPO release for the development of microinflammation in patients on HD.

Topics: Apoptosis; Biocompatible Materials; C-Reactive Protein; Complement System Proteins; Cytokines; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged; Neutrophils; Peroxidase; Renal Dialysis; Ribonuclease, Pancreatic; Serum Amyloid P-Component

Tissue cross-talk is emerging as a determinant way to coordinate the different organs implicated in glucose homeostasis. Among the inter-organ communication factors, muscle-secreted myokines can modulate the function and survival of pancreatic beta-cells. Using primary human myotubes from soleus, vastus lateralis and triceps brachii muscles, we report here that the impact of myokines on beta-cells depends on fiber types and their metabolic status. We show that Type I and type II primary myotubes present specific mRNA and myokine signatures as well as a different sensitivity to TNF-alpha induced insulin resistance. Finally, we show that angiogenin and osteoprotegerin are triceps specific myokines with beta-cell protective actions against proinflammatory cytokines. These results suggest that type I and type II muscles could impact insulin secretion and beta-cell mass differentially in type 2 diabetes through specific myokines secretion.

Topics: Cytokines; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Muscle Cells; Muscle Fibers, Skeletal; Muscle, Skeletal; Osteoprotegerin; Primary Cell Culture; Ribonuclease, Pancreatic; Tumor Necrosis Factor-alpha

Chronic exposure to environmental heavy metals is a worldwide health concern. It is acknowledged to be an important cause of lower respiratory tract damage in children. However, the molecular mechanisms underlying the heavy metal-induced cellular stress/toxicity are not completely understood. Small non-coding RNAs (sncRNAs), such as microRNAs (miRNA) and more recently identified tRNA-derived RNA fragments (tRFs), are critical to the posttranscriptional control of genes. We used deep sequencing to investigate whether cellular sncRNA profiles are changed by environmental heavy metals. We found that the treatment of arsenite, an important groundwater heavy metal, leads to abundant production of tRFs, that are ~30 nucleotides (nts) long and most of which correspond to the 5'-end of mature tRNAs. It is unlikely for these tRFs to be random degradation by-products, as the type of induced tRFs is heavy metal-dependent. Three most inducible tRFs and their roles in arsenite-induced cellular responses were then investigated. We identified that p65, an important transcription factor belonging to NF-κB family and also a key factor controlling inflammatory gene expression, is a regulated target of a tRF derived from 5'-end of mature tRNA encoding AlaCGC (tRF5-AlaCGC). tRF5-AlaCGC activates p65, subsequently leading to enhanced secretion of IL-8 in arsenite response. In this study, we also identified that endonuclease Dicer and angiogenin temporally control the induction of tRF5-AlaCGC, providing an insight into the control of tRF biogenesis and subsequently the prevention of cellular damage.

Topics: Arsenites; Base Sequence; Cell Line; Humans; Inflammation; Metals, Heavy; Respiratory Syncytial Viruses; Ribonuclease III; Ribonuclease, Pancreatic; RNA, Transfer

Sixteen plasma markers of inflammation and oxidative stress were measured during OGTT in 54 subjects. Leptin, RBP4, CRP, OPN, ANG, MDC, and MCSF concentrations significantly decreased during OGTT (P<0.05). IL6, IL8, and MCP3 concentrations significantly increased during OGTT (P<0.05). These results provide evidence that glucose ingestion affects systemic inflammation and oxidative stress.

Topics: Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Chemokine CCL2; Chemokine CCL22; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Osteopontin; Oxidative Stress; Retinol-Binding Proteins, Plasma; Ribonuclease, Pancreatic

Experimental data confirmed that erythropoietin (EPO) administration alters the course of various pathological situations such as heart failure and tumor growth by inducing vascular endothelial growth factor-A (VEGF-A) expression. The effect of EPO dose on plasma VEGF-A level in hemodialysis (HD) patients was evaluated. The effect of EPO dose on plasma angiogenin level in HD patients was also evaluated, since angiogenin is necessary for angiogenesis induced by VEGF-A.. Thirty two HD patients (10 diabetics) enrolled into the study. Patients were iron replete and did not suffer from infections, autoimmune diseases or malignancies. Plasma VEGF-A and angiogenin, as well as serum interleukin-6 and tumor necrosis factor-α were measured by means of ELISA.. Weekly EPO dose per kg of dry body weight was positively related to both VEGF-A and angiogenin, whereas no relation was detected among VEGF-A or angiogenin and hemoglobin, inflammation or presence of diabetes mellitus. These relations among EPO dose and VEGF-A or angiogenin remained after adjustment for hemoglobin concentration or inflammation or presence of diabetes mellitus.. EPO dose may affect plasma VEGF-A and angiogenin concentrations in HD patients.

Topics: Aged; Diabetes Complications; Dose-Response Relationship, Drug; Erythropoietin; Female; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Ribonuclease, Pancreatic; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-α. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O2(-)) scavenger, tempol (400 mg/l in the drinking water), or a TNF-α receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (Δ36 ± 3 mmHg; n = 7), and this effect was attenuated in mice pretreated with tempol (Δ24 ± 3 mmHg; n = 6). In KO mice (n = 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (Δ17 ± 7 mmHg; n = 6) but exaggeratedly in KO (Δ48 ± 12 mmHg, n = 6) associated with severe renal injury. Cotreatment with either tempol (n = 6) or etanercept (n = 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II.

Topics: Angiogenesis Inducing Agents; Angiotensin II; Animals; Hypertension; Inflammation; Male; Mice; Mice, Knockout; Nephritis; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Ribonuclease, Pancreatic; Up-Regulation

Hemodialysis (HD) patients are characterized by impaired T-cell function at least in part because of T-cell zeta-chain downregulation due to inflammation. Angiogenin responds as an acute phase reactant, is increased in HD patients, suppresses T-cell function and increased angiogenin level is co-localized with T-cell zeta-chain downregulation in various pathologies. Angiogenin can inhibit translation of proteins, which lack internal ribosomal entry sites in the corresponding mRNAs. In this study, the possible effect of angiogenin on T-cell zeta-chain downregulation was evaluated. Thirty HD patients and 21 healthy volunteers participated. T-cell zeta-chain expression was assessed with flow cytometry, plasma angiogenin and serum IL-6 with ELISA and serum C-reactive protein with an immunoturbidimetric method. Two available software tools were used for predicting the presence or not of internal ribosomal entry sites in T-cell zeta-chain mRNA sequence. In silico analysis of T-cell zeta-chain mRNA sequence failed to reveal the presence of internal ribosomal entry sites. T-cell zeta-chain expression was lower in HD patients than in healthy volunteers (1.86 ± 0.63 vs. 4.73 ± 3.22). In HD patients, C-reactive protein as well as IL-6 were higher than in healthy volunteers (10.04 ± 15.13 mg/L vs. 3.43 ± 0.98 mg/L and 15.06 ± 13.08 pg/mL vs. 2.11 ± 2.10 pg/mL respectively). Angiogenin was higher in HD patients than in healthy volunteers (483.20 ± 154.07 ng/mL vs. 259.98 ± 64.15 ng/mL). Neither C-reactive protein, nor IL-6 was associated with angiogenin or T-cell zeta-chain expression. Angiogenin concentration was negatively related to the expression of T-cell zeta-chain (r = -0.410, P = 0.025). Increased angiogenin may contribute to decreased T-cell zeta-chain expression in HD patients.

Topics: Aged; Base Sequence; C-Reactive Protein; Case-Control Studies; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Nephelometry and Turbidimetry; Renal Dialysis; Ribonuclease, Pancreatic; RNA, Messenger; T-Lymphocytes

Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis characterized by inflammation and infiltration of eosinophils at the esophageal mucosa. The underlying etiology of EoE remains elusive. Inflammatory diseases, such as asthma, are associated with structural remodeling of the airways, which includes angiogenesis. The aims of this study were to determine the angiogenic profile of esophageal mucosa in children presenting with EoE and to evaluate the putative mechanism(s) underlying the early inflammatory angiogenic response observed in EoE.. Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were analyzed for angiogenic markers (CD31, von Willebrand factor, vascular cell adhesion molecule-1) and tissue levels of angiogenic factors (vascular endothelial growth factor [VEGF]-A, VEGF-R2, angiogenin and interleukin [IL]-8). Expression levels of angiogenic factors and markers in EoE and control samples were characterized by immunofluorescence analysis and quantitative reverse transcriptase-polymerase chain reaction. Vascular density of biopsy samples was evaluated by immunofluorescence analysis.. Samples from patients with EoE exhibited higher levels of von Willebrand factor, CD31, and vascular cell adhesion molecule-1, which is suggestive of neovascularization and an activated endothelium. Moreover, EoE biopsies showed greater levels of the angiogenesis promoters VEGFA, angiogenin, and IL-8. Interestingly, there were greater cellular levels of tumor necrosis factor-α in EoE samples compared with controls. Furthermore, there were higher nuclear levels of p50 and p65 subunits of NFκB and lower cellular levels of the inhibitor of NFκB, IκB-α, in EoE samples compared with controls.. We demonstrate increased angiogenesis in the esophageal mucosa of pediatric patients with EoE. The data also provided evidence that the angiogenic factors VEGF-A, angiogenin, and IL-8 were prominently involved in promoting angiogenic remodeling.

Topics: Biomarkers; Biopsy; Child; Eosinophilic Esophagitis; Esophagus; Female; Humans; I-kappa B Proteins; Inflammation; Inflammation Mediators; Interleukin-8; Male; Mucous Membrane; Neovascularization, Pathologic; NF-kappa B; NF-KappaB Inhibitor alpha; Platelet Endothelial Cell Adhesion Molecule-1; Ribonuclease, Pancreatic; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; von Willebrand Factor

Angiogenesis plays a role in the pathogenesis of coronary heart disease (CHD) and diabetes mellitus (DM) pathology, and certain angiogenic factors are increased by inflammation. The aim of this study was to evaluate plasma angiogenin and vascular endothelial factor A (VEGFA) levels in hemodialysis patients, as well as the effect of CHD, DM, and inflammation on these markers.. Sixty-six hemodialysis patients were enrolled in the study, of whom 22 (33.3%) suffered from CHD , 22 (33.3%) from DM, and 28 (42.4%) from inflammation. They were compared with 24 healthy volunteers. Plasma angiogenin and VEGFA were assessed by means of enzyme-linked immunosorbent assay, and serum C-reactive protein was measured with an immunoturbidimetric method. These markers were compared between hemodialysis patients with and without CHD, DM, and inflammation.. Compared to healthy volunteers, plasma angiogenin was significantly higher in hemodialysis patients (263.57 ± 65.95 ng/mL versus 499.15 ± 175.68 ng/mL; P < .001). Similarly, plasma VEGFA was markedly increased in hemodialysis patients (median, 60.50 pg/mL; range, 280 pg/mL), compared to healthy volunteers (median, 28.84 pg/mL; range, 59.40 pg/mL; P < .001). Neither angiogenin nor VEGFA levels differed significantly between hemodialysis patients with and without CHD, DM, or inflammation.. Plasma angiogenin and VEGFA levels are markedly increased in hemodialysis patients, but not associated with CHD, DM, or inflammation among hemodialysis patients.

Topics: Aged; Biomarkers; C-Reactive Protein; Coronary Disease; Diabetes Mellitus; Humans; Inflammation; Middle Aged; Multivariate Analysis; Renal Dialysis; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

Low-grade inflammation plays a role in the pathogenesis of primary hypertension (PH) and target organ damage (TOD). We evaluated the profile of inflammatory mediators (CRP, RANTES, MIP-1beta, MIP-1alpha, MCP-1, IL-6, angiogenin, adiponectin) in 30 healthy children (12.7 +/- 3.3 years) and 44 patients with untreated PH (13.7 +/- 2.7 years; n.s). Patients had greater concentrations of CRP, MIP-1beta, and RANTES than controls (all p < 0.05). Children with metabolic syndrome (MS) had greater CRP than children without MS (p = 0.007) and CRP correlated with number of MS criteria, body mass index (BMI), visceral fat, deep subcutaneous fat assessed by magnetic resonance imaging, carotid intima-media thickness (cIMT), left ventricular mass index, and markers of oxidative stress. RANTES correlated with cholesterol, LDL cholesterol, ApoB, and ApoB/ApoA1. Angiogenin correlated with BMI, waist circumference, visceral fat, uric acid, and patients with cIMT>2SD had greater concentration of angiogenin than those with normal cIMT (p = 0.03). Adiponectin was lower in patients with cIMT>2SD than in those with normal cIMT (p = 0.02). No model explaining variability of TOD has been built. Elevated RANTES and MIP-1beta and normal IL-6 and TNF-alpha levels indicate a vascular inflammatory process. Lack of correlation between CRP and chemokines suggests that vascular inflammation in PH precedes the systemic inflammatory changes.

Topics: Adiponectin; Adolescent; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Child; Cross-Sectional Studies; Humans; Hypertension; Immunity, Innate; Inflammation; Inflammation Mediators; Interleukin-6; Metabolic Syndrome; Obesity; Poland; Ribonuclease, Pancreatic

Our objective was to assess the regulation of the hypoxia response of angiogenic and inflammatory factors from 76 cerebrospinal fluids (CSF) of sporadic amyotrophic lateral sclerosis (ALS) patients with different respiratory status. We first analysed the hypoxia response capacity by measuring CSF levels of angiogenin (ANG), VEGF, angiopoietin-2 (ANG-2) and PGE-2 in 40 ALS patients according to their hypoxaemia level and compared it with 40 neurological controls. We then compared the ANG, VEGF, EPO and ANG-2 CSF levels of 36 other ALS patients, divided into three groups with either 1) normoxaemia, 2) intermittent desaturation in the absence of hypoxaemia, or 3) chronic hypoxaemia with or without desaturation. We demonstrated a lack of up-regulation of both ANG and VEGF during hypoxaemia in ALS, compared with hypoxaemic controls. In contrast, PGE-2 and ANG-2 levels were increased in both hypoxaemic ALS patients and controls. ANG and VEGF levels did not increase in patients with long disease durations and with intermittent or chronic hypoxaemia. ANG-2 and EPO levels were up-regulated early in intermittent hypoxaemia and late in chronic hypoxaemia, respectively. Our results suggest alteration of the HIF-1alpha-mediated response to hypoxia during sporadic ALS, whereas the NFK-B pathway seems early activated.

Topics: Aged; Amyotrophic Lateral Sclerosis; Angiopoietin-2; Dinoprostone; Erythropoietin; Humans; Hypoxia; Inflammation; Middle Aged; Oxygen; Respiration; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

ANG is a plasma protein with angiogenic and ribonucleolytic activity implicated in tumor growth, heart failure, wound healing, asthma, and the composition of the adult gut microflora. Human mast cells (HuMC) are similarly associated with modulation of vascular permeability, angiogenic processes, wound healing, and asthma. We hypothesized that HuMC express and secrete ANG in response to divergent stimuli. ANG expression was evaluated in the LAD2 HMC, the HMC-1, and CD34+-derived HuMC, following exposure to live Escherichia coli, TLR ligands, or neuropeptides and following FcepsilonRI aggregation. Expression and production of ANG were determined by microarray analysis, qRT-PCR, confocal microscopy, and ELISA. Microarray analysis showed that ANG is up-regulated by LAD2 cells exposed to live E. coli. qRT-PCR analysis revealed that LAD2, HMC-1, and HuMC constitutively expressed ANG mRNA and that it was up-regulated by exposure to E. coli. Activation of HuMC by FcepsilonRI aggregation resulted in release of small amounts of ANG (<100 pg/mL), whereas compound 48/80, NGF, LPS, PGN, and flagellin activated HuMC to secrete >160 pg/mL ANG. These observations demonstrate that HuMC store and secrete ANG to a variety of stimuli and suggest that MC-derived ANG is available in the subsequent inflammatory response.

Topics: Animals; Asthma; Chickens; Escherichia coli; Flow Cytometry; Humans; Inflammation; Mast Cells; Neoplasms; Neovascularization, Physiologic; Oligonucleotide Array Sequence Analysis; Ribonuclease, Pancreatic; Wound Healing

Angiogenin (Ang), a potent mediator of neovascularization, is secreted by and is critical for the growth of human tumor cells in experimental animals. However, control mechanisms that regulate its expression under normal physiological conditions have not been described. We have determined previously that Ang is present in normal human serum and that its concentration, normally falling within a narrow range, can vary widely in hospitalized patients. This observation, plus a report that Ang is synthesized in the adult liver, led us to investigate whether it can be regulated as an acute phase protein (APP). Ang concentration in the serum of mice placed into the acute phase by injection with 3% thioglycollate do indeed increase transiently as is typical for APPs. Moreover, a liver-specific rise and subsequent fall in Ang mRNA transcripts also follows entrance into acute inflammation. We conclude that Ang can be regulated in vivo in a manner that is characteristic of an APP and, therefore, may contribute to the angiogenic component of tissue repair that accompanies host response to inflammation and trauma. To our knowledge, this is the first demonstration that a well-characterized angiogenic mediator can be regulated as an APP.

Topics: Acute-Phase Proteins; Animals; Blotting, Northern; Gene Expression Regulation; Inflammation; Liver; Mice; Protein Biosynthesis; Proteins; Radioimmunoassay; Ribonuclease, Pancreatic; RNA, Messenger; Serum Amyloid A Protein; Thioglycolates; Time Factors