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Daneshmandi S Pourfathollah AA Pourpak Z Heidarnazhad H Kalvanagh PA 《Molecular biology reports》2012,39(2):1845-1853
Asthma is a multifactor inflammatory disorder, and its management requires understanding of its various pathogenesis and control
mechanisms. Cytokines and other inflammatory mediators are important factors in asthma pathophysiology. In this study, we
evaluated the role of cytokine polymorphisms in the asthma susceptibility, progress, control, and lung functions. IL-4-C590T
polymorphism by PCR-RFLP method, IFN-γ T+874A, TNF-α-A308G, IL-6 G−174C and TGF-β T+869C variants by ARMS-PCR method and IgE
serum level by ELISA technique were determined in 81 asthmatic patients and 124 normal subjects. Asthma diagnosis, treatment
and control levels were considered using standard schemes and criteria. TNF-α−308GA genotype was more frequent in asthmatics
(P = 0.025, OR 3.352), and polymorphisms between different asthma control levels (P > 0.05) were not different. IFN-γ+874AT genotype had a positive correlation with the familial history of asthma (P = 0.034, OR 2.688). IL-6−174C allele (P = 0.045), TNF-α−308GG genotype (P = 0.002) and TNF-α−308G allele (P = 0.004) showed reduced values, and TNF-α−308GA genotype (P = 0.002) increased FEF25-75 value in asthmatics. IFN-γ+874AA genotype caused a decrease in FVC factor (P = 0.045). This study showed that TNF-α−308GA is a risk factor for asthma, but cytokine gene variants do not affect asthma
control and IgE serum levels. Variants producing lower levels of IL-6, TNF-α and IFN-γ are associated with reduced pulmonary
capacities. To achieve an appropriate schema for asthma management, further studies with consideration of different aspects
in a larger group of patients would be more elucidative. 相似文献
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Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma 总被引:4,自引:0,他引:4
Akahoshi M Obara K Hirota T Matsuda A Hasegawa K Takahashi N Shimizu M Nakashima K Cheng L Doi S Fujiwara H Miyatake A Fujita K Higashi N Taniguchi M Enomoto T Mao XQ Nakashima H Adra CN Nakamura Y Tamari M Shirakawa T 《Human genetics》2005,117(1):16-26
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Guenterberg KD Lesinski GB Mundy-Bosse BL Karpa VI Jaime-Ramirez AC Wei L Carson WE 《Cancer immunology, immunotherapy : CII》2011,60(9):1281-1288
Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant
setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We
hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections
of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in
response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor
effects of IFN-α in the setting of melanoma. 相似文献
6.
Amim LH Pacheco AG Fonseca-Costa J Loredo CS Rabahi MF Melo MH Ribeiro FC Mello FC Oliveira MM Lapa e Silva JR Ottenhoff TH Kritski AL Santos AR 《Molecular biology reports》2008,35(4):563-566
Several genetic cytokine gene variants have been associated with host susceptibility to infectious diseases, including tuberculosis.
Based upon the importance of IFN-γ in protective immunity against Mycobacterium tuberculosis, and the functional role of the IFN-γ + 874T/A single nucleotide polymorphism in IFN-γ production, we genotyped 93 Brazilian
tuberculosis patients and 266 asymptomatic health care workers, including 150 individuals with a positive tuberculin skin
test, and analyzed the possible association of the +874A low IFN-γ producer allele with tuberculosis occurrence. Using multivariable
logistic regression models, genotype and allele frequencies of the mutant + 874A (low IFN-γ producer) allele were significantly
associated with tuberculosis disease. Heterozygous carriers had a 25% increased chance, while individuals presenting the A/A
homozygous genotype had an over two-fold risk of having active tuberculosis (95% CI, 1.16–5.91, P = 0.03). Despite the mixed ethnicity observed in Brazilian populations, the present data agree with observations reported
in other populations and thus demonstrate that the functional +874T/A IFN-γ gene polymorphism is associated with tuberculosis
in different populations. 相似文献
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Nishijima K Hisatsune T Kato H Kohyama M Kakehi M Hachimura S Kaminogawa S 《Cytotechnology》1997,25(1-3):89-100
Feeding of a whole casein diet, which abolished the αs1-casein-specific proliferation and IFN-γ productivity of CD4+ T cells, did not affect the proliferative response of CD8+ T cells with regard to the antigen dose response, cell dose response, kinetics of the proliferation and epitope specificity,
as well as IFN-γ production. To assess the characteristics of the CD8+ T cells, we established αs1-casein-specific CD8+ T cell clones from both casein-fed and control mice. The established clones produced different amount of IFN-γ and IL-10,
and one clone derived from the casein-fed mice produced a remarkable amount of IL-10. The clones from casein-fed mice produced
considerable amounts of TGF-β, while those from control mice produced only small amounts. The possible role of CD8+ T cells in oral tolerance is discussed.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
8.
Pang YL Zhang HG Peng JR Pang XW Yu S Xing Q Yu X Gong L Yin YH Zhang Y Chen WF 《Cancer immunology, immunotherapy : CII》2009,58(6):877-886
Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. The present study was focused
on analyzing the immune status within hepatocellular carcinoma. In contrast to the increasing number of CD4+ T cells, CD8+, CD3−CD56+, CD3+CD56+, and γδT cells were all found to be under-represented in tumor infiltrating lymphocytes. Notably, the relative abundance
of CD3+CD56+ cells appeared to be correlated with patient survival. Functional analysis demonstrated that CD4+ cells in the tumor tended to produce more IL-10 but less IFN-γ, whereas CD8+ cells showed impaired capacity for the production of both IFN-γ and perforin. Consistent with previous reports, we observed
a significant increase of Foxp3+ cells in the tumor tissue. Intriguingly, although over 90% of CD4+CD25high cells were found to be Foxp3+, the majority of Foxp3+ cells were identified in the CD4+CD25medium and CD4+CD25− subsets. In support of its role as a negative regulator, CD4+CD25high cells suppressed the proliferation of CD4+CD25− cells isolated from the same tissues in an APC dependent manner. In conclusion, the tumor microenvironment of hepatocellular
carcinoma is featured by the presence of multiple immunosuppressive factors. 相似文献
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Miao Yin Liang Zhang Xiao-ming Sun Liu-feng Mao Jie Pan 《Molecular biology reports》2010,37(4):2049-2054
To investigate the effect of apolipoprotein E (apoE) on cytokine expression profile of the liver of young mice, quantitative
RT-PCR (qRT-PCR) assay and cytokine antibody array for multiplex analysis of 62 cytokines have been used to analyze characteristics
of expression of cytokines in the liver of 6-week-old apoE-null (apoE−/−) mice. The levels of plasma cytokines were also analyzed. The mRNA level of IL-1β, IL-2, IL-6, ICAM-1, VCAM-1, MCP-1, NF-κB
(p65), IFN-γ and IκB-α were increased significantly in apoE−/− mice comparative to wild-type (WT) mice. IL-4, IL-10 and GM-CSF, however, were slightly decreased. Compared with WT, levels
of 21 cytokines altered twofold or more in apoE−/− mice, including 10 cytokines increased and 11 decreased. Expression patterns of IL-1β, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-γ
and VCAM-1 showed identical trend between cytokine antibody array and qRT-PCR analysis. Moreover, levels of IL-1β, IFN-γ and
IL-6 in the plasma were elevated, while IL-4 was lightly decreased in apoE−/− mice compared to those in WT mice. These results implied that promotion of type I immune response in the liver of young apoE−/− mice due to alteration of these cytokines, and the phenotypes may be caused by the regulation of NF-κB. The inflammation
and lipid metabolism dysfunction in the liver cooperated in dysfunction of the liver in young apoE−/− mice. 相似文献
12.
Lees CJ Apostolopoulos V Acres B Ong CS Popovski V McKenzie IF 《Cancer immunology, immunotherapy : CII》2000,48(11):644-652
MUC1 is a mucin over-expressed in breast cancer and a proposed target for immunotherapy. By immunising mice with MUC1 conjugated
to mannan (M-FP), CD8+ MHC-class-I restricted cytotoxic T lymphocytes (CTL), of high CTL precursor (CTLp) frequency (1/8000) and with significant
tumour protection, can be induced. The effect of various cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-7, interferon γ (IFNγ),
and granulocyte/macrophage-colony-stimulating factor (GM-CSF)] on the MUC1 CTL immune response was investigated (a) by measuring
the frequencies of CTLp in mice immunised with vaccinia virus constructs containing recombinant cytokines and M-FP, or (b)
by immunising cytokine- or cytokine-receptor-knockout (−/−) mice with M-FP. Vaccinia virus (VV) constructs containing recombinant
cytokines were used either individually or in combination in vivo with M-FP immunisation. M-FP immunisations combined with
VV-IL-2, VV-IL-7 and VV-GM-CSF, and combinations of VV-IFNγ + VV-IL-2, VV-IFNγ + VV-IL-4 or VV-GM-CSF + VV-IL-7 increased
CTLp frequencies up to threefold (1/17 666: M-FP + VV-GM-CSF + VV-IL-7) compared to M-FP (1/77 500) alone. By contrast, M-FP
combined with VV-IL-4 decreased the CTLp frequency threefold whereas VV-IL-6 and VV-IFNγ had no effect. Studies in cytokine-
and cytokine-receptor-gene-knockout (−/−) mice demonstrated that mice that are IL-2 −/− and IL-7 receptor −/− produce the
same CTLp response to M-FP as do control mice, whereas responses in the IL-6 −/−, IL-10 −/− and IFNγ−/− mice were marginally
improved and responses to M-FP in IL-4 −/− and tumour necrosis factor receptor 2 −/− mice were weaker. In spite of the increase
in CTLp frequency, this was not reflected in an in vivo tumour model. Tumour challenges using MUC1+ P815 cells, demonstrated that the addition of cytokines had little additive effect on the already effective tumour-regression
capabilities of M-FP alone.
Received: 24 September 1998 / Accepted: 21 September 1999 相似文献
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Mundy-Bosse BL Young GS Bauer T Binkley E Bloomston M Bill MA Bekaii-Saab T Carson WE Lesinski GB 《Cancer immunology, immunotherapy : CII》2011,60(9):1269-1279
Interferon-alpha (IFN-α) promotes anti-tumor immunity through its actions on immune cells. We hypothesized that elevated percentages
of myeloid-derived suppressor cells (MDSC) and increased pro-inflammatory cytokines in peripheral blood would be associated
with impaired response to IFN-α in patients with gastrointestinal (GI) malignancies. This study evaluated relationships between
plasma IL-6, IL-10, circulating MDSC subsets, and IFN-α-induced signal transduction in 40 patients with GI malignancies. Plasma
IL-6 and IL-10 were significantly higher in patients versus normal donors. CD33+HLADR−CD11b+CD15+ and CD33+HLADR−/lowCD14+ MDSC subsets were also elevated in patients versus normal donors (P < 0.0001). Plasma IL-6 was correlated with CD33+HLADR−CD15+ MDSC (P = 0.008) and IL-10 with CD33+HLADR−CD15− MDSC (P = 0.002). The percentage of CD15+ and CD15− but not CD14+ MDSC subsets were inversely correlated with IFN-α-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFN-α responsiveness in both PBMC and the CD4+ subset of T cells from normal donors. Exploratory multivariable Cox proportional hazards models revealed that an increased
percentage of the CD33+HLADR−CD15− MDSC subset was associated with reduced overall survival (P = 0.049), while an increased percentage of the CD33+HLADR−/lowCD14+ subset was associated with greater overall survival (P = 0.033). These data provide evidence for a unique relationship between specific cytokines, MDSC subsets, and IFN-α responsiveness
in patients with GI malignancies. 相似文献
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Yusuke Nakanishi Akira Hosono Yasuhiro Hiramatsu Teiji Kimura Ryo Nakamura Shuichi Kaminogawa 《Cytotechnology》2005,47(1-3):69-77
We demonstrate immunomodulatory effects, especially those involving murine intestinal IgA secretion, in Peyer's patch cells
following oral administration of Bifidobacterium immunomodulator (BIM) derived from sonicated B. pseudocatenulatum 7041. BALB/c mice were administered BIM orally for 7 consecutive days. The PP cells demonstrated upregulated secretion of
total IgA including BIM-specific IgA following BIM administration. In observing the response of PP cells co-cultured with
BIM, we found enhanced secretion of interferon-γ (IFN-γ) and interleukin (IL)-6 in the CD4+ T cells. In contrast, IL-12 secretion by Thy1.2− PP cells was enhanced, but secretion of IFN-γ, IL-5, and IL-6 was not significantly affected. Furthermore, the population
of CD4+ CD45RBhigh T cells in PP increased following oral administration of BIM. These data suggest that CD4+ T cells were affected by BIM administration. Overall, the results show that oral administration of BIM induced CD4+ PP cells to change their expression of cell surface antigen and cytokine production. 相似文献
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Miki Watanabe Sulaiman Sheriff Theresa A. Ramelot Nijiati Kadeer Junho Cho Kenneth B. Lewis Ambikaipakan Balasubramaniam Michael A. Kennedy 《International journal of peptide research and therapeutics》2011,17(4):281-299
After severe burn injury, proinflammatory cytokine levels are elevated in serum and skeletal muscle, which in turn increases
protein breakdown and decreases protein synthesis. In this study, C2C12 mouse skeletal muscle cell line myotubes were exposed
to proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) as an in vitro cell-line model of catabolic
response to burn injury and then treated with des-acyl ghrelin (DAG), a 28 amino acid polypeptide hormone thought to inhibit
protein breakdown and increase protein synthesis, to assess its therapeutic potential. Nuclear magnetic resonance-based metabonomics
was used to monitor metabolic activity of C2C12 myotubes under four treatment conditions: (1) control, (2) TNF-α/IFN-γ (TI),
(3) DAG (DA), and (4) TNF-α/IFN-γ followed by DAG (TIDA) to assess the effect of DAG treatment on cellular metabolic response
during basal or catabolic conditions. Twelve metabolites showed significant changes in concentrations following treatments
in the hydrophilic cell extracts. Lactate (P < 10−4) and citrulline (P < 10−9) increased with TNF-α/IFN-γ treatment, indicating increased protein degradation, and returned to control levels in the TIDA
group. Adenosine nucleotide levels had decreased trends in TI myotubes that returned to baseline levels after DAG treatment
(P < 10−4). Guanidinoacetate and pantothenate, metabolites involved in protein synthesis and cell proliferation, had increased concentration
trends following DAG treatment in both the DA and TIDA groups. Our metabonomics analysis provides further evidence that DAG
counteracts the catabolic response caused by elevated muscle TNF-α/IFN-γ cytokine levels following severe burns and can play
a potential therapeutic role in treatment of burn injury. 相似文献
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Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment 总被引:1,自引:0,他引:1
Bergmann C Strauss L Zeidler R Lang S Whiteside TL 《Cancer immunology, immunotherapy : CII》2007,56(9):1429-1442
Objective Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory
T cells (Treg). To study the role of Treg in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the
induction and expansion of IL-10+ Treg type 1 (Tr1) was established.
Methods An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic
cells (iDC), CD4+CD25− T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) ± 1 nM rapamycin. Autologous iDC and CD4+CD25− T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating
lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays ± neutralizing
anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-β and IFN-γ in ELISA.
Results In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3+CD4+CD25−IL2Rβ+IL2Rγ+FoxP3+CTLA-4+IL-10+ cells with suppressor activity (mean suppression ± SD = 58 ± 12%). These suppressor cells produced IL-10 (mean ± SD = 535 ± 12 pg/ml)
and TGF-β (mean ± SD = 512 ± 38 pg/ml), but no IL-4 or IFN-γ. Suppressor function of co-cultures correlated with the percent
of expanding IL-10+ Tr1 cells (r
2 = 0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive
activity. Suppression was cell-contact independent.
Conclusion The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4+CD25highFoxP3+ nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical
role in cancer progression. 相似文献
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Production of interferons and change of the lymphocyte subpopulation phenotype in peripheral blood at cervical papillomavirus infection 总被引:3,自引:0,他引:3
Lazarenko L Spivak M Lakatosh V Kryvokhatska L Mikhailenko O Rudenko A Tkáciková L Mikula I 《Folia microbiologica》2002,47(6):747-752
IFN-γ and IFN-α productionin vitro by peripheral blood cells activated by phytohemagglutinin or the Newcastle disease virus was impaired in patients with a
benign process, cervical intraepithelial neoplasm and cancerin situ associated with human papillomavirus infection. In case of IFN-γ and IFN-α production impairment following cervical papillomavirus
infection, the increased severity of disease was accompanied by remarkable IFN system suppression. The lower synthesis of
both IFN correlated with changes of some lymphocyte-subpopulation phenotype in peripheral blood. Lower CD4+ and CD3+ DR+ T cell concentrations were observed in papillomavirus-infected patients with impaired IFN production; impaired IFN-γ production
was accompanied by lower CD4/CD8 index. 相似文献
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Perambakam S Hallmeyer S Reddy S Mahmud N Bressler L DeChristopher P Mahmud D Nunez R Sosman JA Peace DJ 《Cancer immunology, immunotherapy : CII》2006,55(9):1033-1042
T cell immunotherapy of prostate cancer (CaP) offers the potential for less toxic, more effective outcomes. A clinical trial was conducted in 28 patients with locally advanced or metastatic CaP to determine whether an HLA-A2 binding epitope of prostate-specific antigen, PSA146–154 (PSA-peptide), can induce specific T cell immunity. Patients were vaccinated either by intradermal injection of PSA-peptide and GM-CSF or by intravenous administration of autologous dendritic cells pulsed with PSA-peptide at weeks 1, 4 and 10. Delayed-type hypersensitivity (DTH) skin testing was performed at weeks 4, 14, 26 and 52. Fifty percent of the patients developed positive DTH responses to PSA-peptide. The size of the DTH induration progressively increased over time in the majority of responding patients. Skin biopsies from seven DTH-positive patients were available and T cells that developed in situ were also characterized. The phenotype of recovered T cells demonstrated variable proportions of CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell populations. Cytokine analysis of PSA-peptide stimulated T cells per bead array assay exhibited specific IFN-γ and TNF-α response in six of seven patients. Specific IL-4 response was observed in five patients, while IL-10 response was detected in one patient. Purified CD4−CD8+ T cells isolated from four patients demonstrated specific cytolytic activity per chromium release assay. In conclusion, immunization with PSA-peptide induced specific T cell immunity in one-half of the patients with locally advanced and hormone-sensitive, metastatic CaP. DTH-derived T cells exhibited PSA-peptide-specific cytolytic activity and predominantly expressed a type-1 cytokine profile. 相似文献
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Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献