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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have hypothesized that T cell cytokines participate in the pathogenesis of graft arterial disease (GAD). This study tested the consequences of IFN-gamma deficiency on arterial and parenchymal pathology in murine cardiac allografts. Hearts from C-H-2(bm12)KhEg (bm12, H-2(bm12)) were transplanted into C57/B6 (B6, H-2(b)), wild-type, or B6 IFN-gamma-deficient (GKO) recipients after immunosuppression by treatment with anti-CD4 and anti-CD8 mAbs. In wild-type recipients, myocardial rejection peaked at 4 wk, (grade 2. 1+/-0.3 out of 4, mean+/-SEM, n = 9), and by 8-12 wk evolved coronary arteriopathy. At 12 wk, the GAD score was 1.4+/-0.3, and the parenchymal rejection grade was 1.2+/-0.3 (n = 8). In GKO recipients of bm12 allografts, myocardial rejection persisted at 12 wk (grade 2.5+/-0.3, n = 6), but no GAD developed (score: 0.0+/-0.0, n = 6, P < 0.01 vs. wild-type). Mice treated with anti-IFN-gamma mAbs showed similar results. Isografts generally showed no arterial changes. In wild-type recipients, arterial and parenchymal cells showed increased MHC class II molecules, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 compared to normal or isografted hearts. The allografts in GKO recipients showed attenuated expression of these molecules (n = 6). Thus, development of GAD, but not parenchymal rejection, requires IFN-gamma. Reduced expression of MHC antigens and leukocyte adhesion molecules may contribute to the lack of coronary arteriopathy in hearts allografted into GKO mice.
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PMID:Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. 923 1

To investigate the functional role of interferon (IFN)-gamma in transplant arteriosclerosis, BALB/c hearts were transplanted in immunosuppressed C57BL/6J recipients with (n = 10) or without (n = 10) targeted IFN-gamma gene deletion. In 55-day heart allografts, IFN-gamma deficiency resulted in a significant decrease in vascular thickening. The severity of intimal thickening measured as the percentage of luminal occlusion (mean +/- SEM) in all elastin stained vessels (n = 410) decreased from 37+/-5% in wild-type recipients to 18+/-5% in IFN-gamma -/- recipients (P < 0.005). In the few diseased vessels in grafts from IFN-gamma -/- recipients, the neointima was more cellular with a 90% increase in the nuclear density. This finding correlated with a 50% reduction in fibrosis estimated by alpha-smooth muscle actin cell accumulation in the neointima. The reduction in severity and altered composition of vascular thickening in grafts from IFN-gamma -/- recipients shows that IFN-gamma contributes to arteriosclerotic development following transplantation.
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PMID:Reduced transplant arteriosclerosis in murine cardiac allografts placed in interferon-gamma knockout recipients. 946 61

Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.
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PMID:Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. 961 86

Atopic dermatitis (AD) is associated with increased IL-4, IL-5, and IL-13 but decreased IFN-gamma production. This cytokine profile may account for the atopic features of this illness, including IgE upregulation. Recent studies have demonstrated that tumor necrosis factor (TNF)-beta is produced by Th1-like cells, but the cytokine modulation by TNF-beta and the clinical significance of this cytokine in AD is not known. Therefore, this study was carried out to determine the potential role of TNF-beta in AD. In this study, we cultured peripheral blood mononuclear cells from patients with AD and normal subjects with anti-CD3 monoclonal antibodies and investigated the production of TNF-beta by ELISA. The mean +/- SEM of TNF-beta production in AD was significantly lower than normal subjects (p = 0.03). The effect of TNF-beta on cytokine production was investigated by culturing peripheral blood mononuclear cells with anti-CD3 monoclonal antibodies in the presence or absence of TNF-beta. Compared with medium control, TNF-beta significantly decreased IL-5 (p = 0.0004) and IL-13 (p = 0.008) but increased IFN-gamma (p = 0.001) production. The effect of TNF-beta on IgE production was determined by culturing peripheral blood mononuclear cells in the IL-4- and anti-CD40-induced IgE production system. Interestingly, TNF-beta significantly decreased IgE (p = 0.02), but not IgG production compared with medium control. Our study demonstrates that TNF-beta production is downregulated in AD. This cytokine increases IFN-gamma production but decreases IL-5, IL-13, as well as IgE production. These findings suggest a potential role for TNF-beta in the pathogenesis of AD.
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PMID:The modulation of cytokine and IgE production by tumor necrosis factor-beta in atopic dermatitis. 1062 Jan 39

Chronic beryllium disease (CBD) results from exposure to the light-weight metal beryllium (Be). In vitro stimulation of bronchoalveolar lavage cells from CBD subjects causes the production of high levels of TNF-alpha, IFN-gamma and IL-6. We tested the hypothesis that Be-stimulation might induce the production of TNF-alpha by macrophage cell lines. We observed that H36.12j cells (12j), a mouse hybrid macrophage cell line, but not other mouse and human macrophage cell lines, produced TNF-alpha upon Be-stimulation. The response was maximal at 100 microM BeSO4 and did not occur when 12j cells were stimulated with either aluminum sulfate or cobalt sulfate. Beryllium-stimulated the production of 725+/-25 pg/ml (mean +/- SEM) TNF-alpha protein by 12j cells as measured by ELISA of culture supernatants after 24 h. As measured by RT-PCR, Be-stimulated 12j cell TNF-alpha protein production was accompanied by an increased intracellular TNF-alpha mRNA at 3 and 24 h. The addition of 10U or 100U of rMu-IFN-gamma to Be-stimulated 12j cells further increased TNF-alpha production 1.5-4 fold (1.6+/-0.1 ng/ml) respectively. Bacterial lipopolysaccharide (LPS, 1 microg/ml) stimulated production of TNF-alpha in 12j culture supernatants after 6 h (515+/-151 pg/ml). This early versus late TNF-alpha production suggests that LPS and Be both stimulate 12j cell TNF-alpha synthesis, but through different pathways. We report for the first time, the direct effects of Be stimulation on the ability of 12j cells to produce TNF-alpha. The 12j cell line, contrasted with other macrophage hybrids that do not respond to Be-stimulation, may provide a useful tool to evaluate the mechanisms by which Be stimulates macrophage cytokine production, and by which T cell derived IFN-gamma amplifies TNF-alpha production in granulomatous diseases.
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PMID:Beryllium-stimulated production of tumor necrosis factor-alpha by a mouse hybrid macrophage cell line. 1075 10

We tested the hypothesis that beryllium (Be) could stimulate H36.12j cell (12j) TNF-alpha production by transcription factor-mediated pathways similar to those induced by either LPS- or IFN-gamma stimulation. Unstimulated 12j cells produce constitutive levels of TNF-alpha (175+/-18 pg/ml, mean +/- SEM) detected by ELISA of culture supernatants after 24 h. Beryllium-stimulated (100 microM BeSO4) 12j cell TNF-alpha (724+/-47 pg/ml) was observed after 24 h while LPS-stimulated (1 microg/ml) TNF-alpha (515+/-151 pg/ml) after 6 h. Recombinant-Mu-IFN-gamma (10 U) stimulated 12j cell TNF-alpha at lower levels (284+/-31 pg/ml) while rMu-IFN-gamma + Be-stimulated 12j cells produced 1195+/-225 pg/ml TNF-alpha. Constitutive levels of transcription factors were observed in unstimulated 12j cell nuclei. In LPS-stimulated 12j cells IkappaBalpha was degraded in the cytoplasm and increased levels of NF-kappaB were found in nuclei after 30 min. After 3 h there were increased levels of AP-1 and CREB, with increased amounts of Fos family, Jun B and Jun D transcription factors. In contrast, Be-stimulation failed to increase the levels of any transcription factor tested, NF-kappaB, AP-1, AP-2, CREB, C/EBP, Sp-1, Egr-1, Ets, NF-Y or Oct-1, in 12j cells. A pattern of increased transcription factors, similar to that observed for LPS-stimulation, was found in 12j cell nuclei after stimulation with rMu-IFN-gamma. However, NF-kappaB was increased at 3 h while AP-1 (Jun B and Jun D) and CREB were increased at 15 h. Co-stimulation of 12j cells with rMu-IFN-gamma + Be increased the levels of NF-KB in 12j cell nuclei at 3 h, and the levels of AP-1 and CREB at 15 h, however, only Jun B was increased. Our data show 12j cell TNF-alpha production was associated with increased levels of transcription factors present in nuclei with disparate kinetics and patterns of expression depending on the trigger. We reject our initial hypothesis and conclude that Be-stimulation signals 12j cell TNF-alpha synthesis via a transcription factor-independent pathway. Beryllium may induce novel pathways of macrophage cytokine gene regulation.
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PMID:Beryllium-stimulation does not activate transcription factors in a mouse hybrid macrophage cell line. 1075 11

Quantitative aspects of the in-vitro interferon (IFN)-gamma-induced nitric oxide (NO) production by peritoneal macrophages of eight inbred strains of mice were investigated. Animals employed in the study can be assorted into three phenotype categories: high, moderate, and low NO-responders. Concentration of nitrites in the 24-h supernatants of cells stimulated with recombinant murine IFN-gamma (25 U/ml) reached the following values (mean +/- SEM; in microM): C57BL/10 (33.7+/-1.88) = C57BL/6 (32.1+/-2.10) > SIL (24.0+/-1.55) > CBA/J (18.1+/-1.79) = C3H/HeN (18.0+/-1.10) > DBA/2 (11.4+/-1.16) = DBA/1 (11.0+/-1.20) = Balb/c (11.0+/-1.16). Approximately 80% of the total variation was found to be controlled by genetic factors. No association between the extent of NO formation and variation in the constitutive expression of macrophage IFN-gamma receptor was observed. Similar magnitude of inter-strain differences was sustained after enhanced NO-stimulation of the cells with IFN-gamma + tumour necrosis factor (TNF)-alpha, but only high (strains BL/10, BL/6, SJL, CBA/J, C3H/HeN) and low (DBA/1, DBA/2, Balb/c) NO-responder phenotypes were detected after the triple cytokine cocktail composed of IFN-gamma + TNF-alpha + interleukin (IL)-10. The strain differences remained unchanged after the supplementation of culture medium with L-arginine or tetrahydrobipopterin. Genetically governed differences in IFN-gamma-induced NO production have been found to be tightly associated with differential expression of inducible nitric oxide synthase mRNA. Possible implications of the findings for various fields of NO biomedical research are discussed.
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PMID:Genetic variation in in-vitro cytokine-induced production of nitric oxide by murine peritoneal macrophages. 1097 3

We have reported an autoantibody response in ulcerative colitis (UC) against human tropomyosin isoform 5 (hTM5), the predominant colonic epithelial cell hTM isoform. In this report, we determined the number of IFN-gamma-secreting cells (spot-forming cells, SFC) against hTM5 by an enzyme-linked immunospot (ELISPOT) assay. Another cytoskeletal protein, caldesmon, CaD40, was used as a control antigen. Peripheral blood mononuclear cells were separated by a Ficoll density gradient from 28 patients with UC, 13 patients with Crohn's disease (CD), and 9 healthy subjects (HS). The mean (+/-SEM) SFC values against hTM5 in UC, CD, and HS were 48.8 +/- 8.1, 18.6 +/- 4.6, and 20.8 +/- 8.6, respectively. The value in UC was significantly higher than those in CD (P < 0.005) and HS (P < 0.025). SFC values in CD did not differ from those in HS. None of the 50 samples (except 1 UC) reacted to the CaD40 antigen. This study demonstrates, for the first time, a defined colon epithelial cell antigen, hTM5, that is capable of inducing a significant T cell response in UC but not in CD.
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PMID:Cellular immune response against tropomyosin isoform 5 in ulcerative colitis. 1172 21

Leukotrienes play a critical role in promoting bronchoconstriction in asthma. The purpose of this study was to examine whether interferon (IFN)-gamma, a cytokine upregulated in asthmatic airways, modulates leukotriene (LT)D4 receptor expression and contractile responses in cultured human airway smooth muscle (HASM) cells. Treatment of HASM cells with IFN-gamma (10 to 1,000 U/ml) stimulated a dose-dependent increase in cell-surface expression of cysteinyl leukotriene receptor 1 (CysLT1) as determined by flow cytometry. CysLT1 messenger RNA (mRNA) levels were also significantly enhanced by IFN-gamma, as demonstrated by reverse transcription-polymerase chain reaction. To determine the functional relevance of increased CysLT1 expression in HASM, cell stiffness responses to LTD4 were measured with magnetic twisting cytometry. IFN-gamma (1,000 U/ml for 24 h) markedly increased LTD4-induced changes in cell stiffness, from 4.6 +/- 1 [mean +/- SEM]% to 24.4 +/- 3.7% (n = 8, p < 0.05). Montelukast, a CysLT1 antagonist, completely inhibited LTD4-induced increases in cell stiffness. IFN-gamma had no effect on the cell stiffness responses to bradykinin, another contractile agonist. Collectively, these data suggest that IFN-gamma increases LTD4 responses in HASM cells by increasing cell-surface expression of CysLT1. Our data suggest that increased levels of IFN-gamma in asthmatic individuals may promote airway hyperresponsiveness and asthma exacerbations by directly modulating contractile responses of HASM.
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PMID:Interferon-gamma modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes. 1173 41

Activated myelin-specific T cells are thought to mediate inflammatory tissue damage in multiple sclerosis (MS). Applying a large panel of myelin antigens, we demonstrate the direct ex vivo detection of viable IFN-gamma/TNF-alpha producing CD4+/CD69+ T cells 6 hours after antigenic challenge, by intracellular flow cytometry in 3/33 MS patients and 2/26 healthy controls with calculated frequencies of (mean +/- SEM): 0.031% +/- 0.002% versus 0.037% +/- 0.029%. By comparison, the recently developed IL-7 modified proliferation assay revealed i) a higher number of individuals showing myelin reactivity (17/37 MS patients and 12/24 healthy individuals) and ii) a significant difference in the response to myelin basic protein (MBP) between the two groups in a longitudinal analysis, indicating a higher activity of myelin-specific T cells in MS patients. Our data provide new perspectives in detecting pathogenetically relevant T cells, but clearly demonstrate the different conclusions which must be drawn from various approaches concerning the quantification of autoreactive T cells.
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PMID:Cross-sectional and longitudinal analysis of myelin-reactive T cells in patients with multiple sclerosis. 1537 55


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