952 resultados para gamma interferon inducible protein 10
Resumo:
Intense inflammatory response and an anti-angiogenic state have been implicated in the pathogenesis of preeclampsia. Here, we investigated this hypothesis evaluating the serum concentrations of CXCL10/IP-10, sFlt-1, and PlGF in women with early-onset preeclampsia. CXCL10/IP-10 was measured by Cytometric Bead Array. sFlt-1 and PlGF were measured by automated electrochemiluminescence immunoassay. The median serum concentration of CXCL10/IP-10 was 109.5 pg/mL in preeclamptic women, as compared with 52.28 pg/mL in the controls (P = 0.0028). The mean serum level of sFlt-1 was 13,636 pg/mL in preeclamptic women, as compared with 2020 pg/mL in the controls (P < 0.0001). PlGF levels were significantly lower in women with preeclampsia. © 2011 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
Resumo:
Interferons (IFNs) have been shown to exert antiviral, cell growth regulatory, and immunomodulatory effects on target cells. Both type I (α and β) and type II (γ) IFNs regulate cellular activities by specifically inducing the expression or activation of endogenous proteins that perform distinct biological functions. p202 is a 52 kDa nuclear phosphoprotein known to be induced by IFNs. p202 interacts with a variety of cellular transcription and growth regulatory factors and affects their functions. ^ In this report, we showed that the expression of p202 was associated with an anti-proliferative effect on human prostate cancer cells. Cells that expressed p202 showed reduced ability to grow in soft-agar, indicating a loss of transformation phenotype. More importantly, p202 expression reduced the tumorigenicity of human prostate cancer cells. p202-expressing cells exhibit an elevated level of hypophosphorylated form of pRb, and reduced level of cyclin B1 and p55CDC. ^ Our data suggest that p202 is a growth inhibitor gene in prostate cancer cells and its expression may also suppress transformation phenotype and tumorigenicity of prostate cancer cells. ^ In addition to inhibiting in vitro cell growth, suppressing the tumorigenicity of breast cancer cells in vivo, p202 expression could sensitize breast cancer cells to apoptosis induced by TNF-α treatment. One possible mechanism contributing to this sensitization is the inactivation of NF-κB by its interaction with p202. These results provide a scientific basis for a novel therapeutic strategy that combines p202 and TNF-α treatment against breast cancer. ^ It has been reported that NF-κB is constitutively active in human pancreatic cancer cells. Since p202 interacts with NF-κB and inhibits its activity, we examined a potential p202-mediated anti-tumor activity in pancreatic cancer. We used both ectopic and orthotopic xenograft models and demonstrated that p202 expression is associated with multiple anti-tumor activities that include inhibition of tumor growth, reduced tumorigenicity, prolonged survival, and remarkably, suppression of metastasis and angiogenesis. In vitro invasion assay also showed that p202-expressing pancreatic cancer cells are less invasive than those without p202 expression. That observation was supported by the findings that p202-expressing tumors showed reduced expression of angiogenic factors such as IL-8, and VEGF by inhibiting their transcription, and p202-expressing pancreatic cancer cells have reduced level of MAP-2 activity, a secreted protease activity important for metastasis. Together, our results strongly suggest that p202 expression mediates multiple anti-tumor activities against pancreatic cancer, and that may provide a scientific basis for developing a p202-based gene therapy in pancreatic cancer treatment. ^ Importantly, we demonstrated a treatment efficacy by using p202/SN2 liposome complex in a nude mice orthotopic breast cancer, and an ectopic pancreatic cancer xenograft model, through systemic and intra-tumor injection respectively. These results suggest a feasibility of using p202/SN2 liposome in future pre-clinical gene therapy experiments. ^
Resumo:
A role for infection and inflammation in atherogenesis is widely accepted. Arterial endothelium has been shown to express heat shock protein 60 (HSP60) and, since human (hHSP60) and bacterial (GroEL) HSP60s are highly conserved, the immune response to bacteria may result in cross-reactivity, leading to endothelial damage and thus contribute to the pathogenesis of atherosclerosis. In this study, GroEL-specific T-cell lines from peripheral blood and GroEL-, hHSP60-, and Porphyromonas gingivalis-specific T-cell lines from atherosclerotic plaques were established and characterized in terms of their cross-reactive proliferative responses, cytokine and chemokine profiles, and T-cell receptor (TCR) V beta expression by flow cytometry. The cross-reactivity of several lines was demonstrated. The cytokine profiles of the artery T-cell lines specific for GroEL, hHSP60, and P. gingivalis demonstrated Th2 phenotype predominance in the CD4 subset and Tc0 phenotype predominance in the CD8 subset. A higher proportion of CD4 cells were positive for interferon-inducible protein 10 and RANTES, with low percentages of cells positive for monocyte chemoattractant protein 1 and macrophage inflammatory protein la, whereas a high percentage of CD8 cells expressed all four chemokines. Finally, there was overexpression of the TCR V beta 5.2 family in all lines. These cytokine, chemokine, and V beta profiles are similar to those demonstrated previously for P. gingivalis-specific lines established from periodontal disease patients. These results support the hypothesis that in some patients cross-reactivity of the immune response to bacterial HSPs, including those of periodontal pathogens, with arterial endothelial cells expressing hHSP60 may explain the apparent association between atherosclerosis and periodontal infection.
Resumo:
OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.
Resumo:
Objective: To simultaneously evaluate 14 biomarkers from distinct biological pathways for risk prediction of ischemic stroke, including biomarkers of hemostasis, inflammation, and endothelial activation as well as chemokines and adipocytokines.
Methods and Results: The Prospective Epidemiological Study on Myocardial Infarction (PRIME) is a cohort of 9771 healthy men 50 to 59 years of age who were followed up over 10 years. In a nested case–control study, 95 ischemic stroke cases were matched with 190 controls. After multivariable adjustment for traditional risk factors, fibrinogen (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03–2.28), E-selectin (OR, 1.76; 95% CI, 1.06–2.93), interferon-γ-inducible-protein-10 (OR, 1.72; 95% CI, 1.06–2.78), resistin (OR, 2.86; 95% CI, 1.30–6.27), and total adiponectin (OR, 1.82; 95% CI, 1.04–3.19) were significantly associated with ischemic stroke. Adding E-selectin and resistin to a traditional risk factor model significantly increased the area under the receiver-operating characteristic curve from 0.679 (95% CI, 0.612–0.745) to 0.785 and 0.788, respectively, and yielded a categorical net reclassification improvement of 29.9% (P=0.001) and 28.4% (P=0.002), respectively. Their simultaneous inclusion in the traditional risk factor model increased the area under the receiver-operating characteristic curve to 0.824 (95% CI, 0.770–0.877) and resulted in an net reclassification improvement of 41.4% (P<0.001). Results were confirmed when using continuous net reclassification improvement.
Conclusion: Among multiple biomarkers from distinct biological pathways, E-selectin and resistin provided incremental and additive value to traditional risk factors in predicting ischemic stroke.
Resumo:
Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.
Resumo:
Tumor necrosis factor alpha (TNF-alpha) is well-characterized for its necrotic action against tumor cells; however, it has been increasingly associated with an apoptosis-inducing potential on target cells. While the signaling events and the actual cytolytic mechanism(s) for both TNF-alpha-induced necrosis and apoptosis remain to be fully elucidated, we report here on (i) the ability of TNF-alpha to induce apoptosis in the promonocytic U937 cells, (ii) the discovery of a cross-talk between the TNF-alpha and the interferon signaling pathways, and (iii) the pivotal role of interferon-inducible, double-stranded RNA-activated protein kinase (PKR) in the induction of apoptosis by TNF-alpha. Our data from microscopy studies, trypan blue exclusion staining, and apoptotic DNA ladder electrophoresis revealed that a subclone derived from U937 and carrying a PKR antisense expression vector was resistant to TNF-alpha-induced apoptosis. Further, TNF-alpha initiated a generalized RNA degradation process in which the participation of PKR was required. Finally, the PKR gene is a candidate "death gene" since overexpression of this gene could bring about apoptosis in U937 cells.
Resumo:
Grass carp hemorrhagic virus (GCHV)-induced gene 2 (Gig2) is a novel gene previously identified from UV-inactivated GCHV-treated Carassius auratus blastulae embryonic (CAB) cells, suggesting that it should play a pivotal role in the interferon (IFN) antiviral response. In this study, a polyclonal anti-Gig2 antiserum was generated and used to study the inductive expression pattern by Western blot analysis, showing no basal expression in normal CAB cells but a significant up-regulation upon UV-inactivated GCHV, polyinosinic:polycytidylic acid (Poly I:Q and recombinant IFN (rIFN). However, constitutive expression of Gig2 is observed in all tested tissues from grass carp (Ctenopharyngodon idellus), and Poly I:C injection increases the relative amount of Gig2 protein in skin, spleen, trunk kidney, gill, hindgut and thymus. Moreover, the genomic sequence covering the whole Gig2 ORF and the upstream promoter region were amplified by genomic walking. Significantly, the Gig2 promoter contains three IFN-stimulated response elements (ISREs), nine GAAA/TfTC motifs and five gamma-IFN activating sites (GAS), which are the characteristics of genes responsive to both type I IFN and type 11 IFN. Subsequently, the complete Gig2 promoter sequence was cloned into pGL3-Basic vector, and its activity was measured by luciferase assays in the transfected CAB cells. The Gig2 promoter-driven construct is highly induced in CAB cells after treatment with Poly I:C or rIFN, and the functional capability is dependent on IFN regulatory factor 7 (IRF7), because its activity can be stimulated by IRF7. Collectively, the data provide strong evidence that Gig2 is indeed a novel IFN inducible gene and its expression is likely dependent on IRF7 upon Poly I:C or IFN. (C) 2009 Elsevier Ltd. All rights reserved.
Resumo:
Antigen-specific gamma interferon (IFN-gamma) has been demonstrated to participate in protection against Bordetella pertussis infection. Circulating mononuclear cells from B. pertussis-infected and from pertussis-vaccinated infants secrete high amounts of IFN-gamma after in vitro stimulation by B. pertussis antigens, but with a large variation in the secreted IFN-gamma levels between individuals. We show here that the inhibition of the specific IFN-gamma response can be at least partially attributed to IL-10 secretion by monocytes. This IL-10 secretion was not associated with polymorphisms at positions -1082, -819, and -592 of the IL-10 gene promoter, suggesting that other genetic or environmental factors affect IL-10 expression and secretion.
Resumo:
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Resumo:
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Resumo:
Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-alpha) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B(L) inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B(S) and A3C had no effect. A3B(L) and A3B(S) were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV.
Resumo:
The aim of the present study was to evaluate the potential of diagnostic tests based on interferon-gamma inducible protein (IP)-10 and monocyte chemotactic protein (MCP)-2, and compare the performance with the QuantiFERON TB Gold In-Tube (QFT-IT; Cellestis, Carnagie, Australia) test. IP-10 and MCP-2 were determined in supernatants from whole blood stimulated with Mycobacterium tuberculosis-specific antigens. Samples were obtained from 80 patients with culture- and/or PCR-proven tuberculosis (TB), and 124 unexposed healthy controls: 86 high school students and 38 high school staff. IP-10 and MCP-2 test cut-offs were established based on receiver operating characteristic curve analysis. TB patients produced significantly higher levels (median) of IP-10 (2158 pg x mL(-1)) and MCP-2 (379 pg x mL(-1)) compared with interferon (IFN)-gamma (215 pg x mL(-1)). The QFT-IT, IP-10 and MCP-2 tests detected 81, 83 and 71% of the TB patients; 0, 3 and 0% of the high school students and 0, 16 and 3% of the staff, respectively. Agreement between tests was high (>89%). By combining IP-10 and IFN-gamma tests, the detection rate increased among TB patients to 90% without a significant increase in positive responders among the students. In conclusion, interferon-gamma inducible protein-10 and monocyte chemotactic protein-2 responses to Mycobacterium tuberculosis-specific antigens could be used to diagnose infection. Combining interferon-gamma inducible protein-10 and interferon-gamma may be a simple approach to increase the detection rate of the Mycobacterium tuberculosis-specific in vitro tests.
Resumo:
The interferon-inducible double-stranded (ds) RNA-activated protein kinase (PKR) exhibits antiviral, anticellular, and antitumor activities. The mechanisms of its enzymatic activation by autophosphorylation and of the observed transdominant inhibitory phenotype of enzymatically inactive mutants have invoked PKR dimerization. Here we present direct evidence in support of PKR-PKR interaction. We show that radiolabeled PKR can specifically interact with matrix-bound unlabeled PKR in the absence of dsRNA. The self-association activity resides, in part, in the N-terminal region of 170 residues, which also constitutes the dsRNA-binding domain (DRBD). DRBD can bind to matrix-bound PKR or to matrix-bound DRBD. Dimerization of DRBD was directly demonstrated by chemical crosslinking. Affinity chromatography and electrophoretic mobility supershift assays demonstrated that mutants that fail to bind dsRNA can still exhibit protein-protein interaction. The PKR-PKR interaction could also be observed in a two-hybrid transcriptional activation assay in mammalian cells and consequently is likely to be an important feature of PKR activity in vivo.
Resumo:
Bacterial lipopolysaccharide (endotoxin) is a frequent contaminant of biological specimens and is also known to be a potent inducer of beta-chemokines and other soluble factors that inhibit HIV-1 infection in vitro. Though lipopolysaccharide (LPS) has been shown to stimulate the production of soluble HIV-1 inhibitors in cultures of monocyte-derived macrophages, the ability of LPS to induce similar inhibitors in other cell types is poorly characterized. Here we show that LPS exhibits potent anti-HIV activity in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs) but has no detectable anti-HIV-1 activity in TZM-bl cells. The anti-HIV-1 activity of LPS in PBMCs was strongly associated with the production of beta-chemokines from CD14-positive monocytes. Culture supernatants from LPS-stimulated PBMCs exhibited potent anti-HIV-1 activity when added to TZM-bl cells but, in this case, the antiviral activity appeared to be related to IFN-gamma rather than to beta-chemokines. These observations indicate that LPS stimulates PBMCs to produce a complex array of soluble HIV-1 inhibitors, including beta-chemokines and IFN-gamma, that differentially inhibit HIV-1 depending on the target cell type. The results also highlight the need to use endotoxin-free specimens to avoid artifacts when assessing HIV-1-specific neutralizing antibodies in PBMC-based assays.