scholarly journals Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production.

1995 ◽  
Vol 181 (2) ◽  
pp. 537-546 ◽  
Author(s):  
A D'Andrea ◽  
X Ma ◽  
M Aste-Amezaga ◽  
C Paganin ◽  
G Trinchieri
Keyword(s):  
Tumor Necrosis Factor ◽  
Peripheral Blood ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Inhibitory Effects ◽  
Peripheral Blood Mononuclear ◽  
Cell Functions ◽  
Necrosis Factor

The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.

scholarly journals Tumor necrosis factor alpha is a potent synergistic factor for the proliferation of primitive human hematopoietic progenitor cells and induces resistance to transforming growth factor beta but not to interferon gamma.

1996 ◽  
Vol 183 (2) ◽  
pp. 705-710 ◽  
Author(s):  
H W Snoeck ◽  
S Weekx ◽  
A Moulijn ◽  
F Lardon ◽  
M Lenjou ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Hematopoietic Progenitor Cells ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Inhibitory Effects ◽  
Hematopoietic Progenitor ◽  
Ifn Gamma ◽  
Kit Ligand ◽  
Necrosis Factor

Since tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta have all been shown to be specific inhibitors of early human hematopoiesis, we wanted to investigate the interactions of these three cytokines on very primitive human adult bone marrow CD34++CD38- hematopoietic progenitor cells, using a pre-colony-forming cell (pre-CFC) assay, which detects the effects of these cytokines on the initial phases of the differentiation of these primitive progenitors, which are unresponsive to interleukin (IL) 3 alone. Surprisingly, TNF-alpha was a very potent stimulator of the proliferation of CD34++CD38- cells and was the most potent synergistic factor for the IL-3-induced proliferation of these cells of all cytokines tested (IL-1, IL-6, granulocyte colony-stimulating factor, kit ligand). TNF-alpha was the only cytokine that, as a single added factor, induced substantial proliferation in CD34++CD38- cells in the presence of IL-3, except for kit ligand, which induced very limited proliferation. TNF-alpha, moreover, induced a high degree of resistance to the inhibitory effects of TGF-beta in a dose-dependent way. The inhibitory effects of IFN-gamma, however, were not affected by the presence of TNF-alpha. We hypothesize that in situations of the hematopoietic stress, TNF-alpha may abrogate the inhibitory effect of ambient TGF-beta in the bone marrow microenvironment to allow primitive stem cells to proliferate and differentiate in response to an increased demand for mature blood cells.

scholarly journals Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha.

1987 ◽  
Vol 166 (4) ◽  
pp. 991-998 ◽  
Author(s):  
G E Ranges ◽  
I S Figari ◽  
T Espevik ◽  
M A Palladino
Keyword(s):  
Transforming Growth Factor Beta ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Inhibitory Effects ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Growth Factor Beta ◽  
Necrosis Factor

The immunoregulatory effects of transforming growth factor beta (TGF-beta) and recombinant murine tumor necrosis factor alpha (rMuTNF-alpha) on CTL generation and activity were examined. The results demonstrate that TGF-beta, in a dose-dependent manner, inhibited CTL generation but not CTL activity. The inhibitory effects were detected only when TGF-beta was added within the first 48 h of the MLC. Little activity was seen when it was added thereafter, including the addition of TGF-beta to the cytotoxicity assay. The production of TNF-alpha, which occurs during early phases of the MLC and which is inhibited in the presence of TGF-beta, appears to have an important regulatory role, as altering the levels of TNF-alpha in an MLC can significantly influence CTL development. The inhibitory effects of TGF-beta on the MLC can be significantly reversed by the addition of rMuTNF-alpha to the cultures. These results demonstrate that TGF-beta can inhibit MLC and subsequent CTL generation at early stages of the reaction, and such inhibition may involve the suppression of TNF-alpha production.

Polymorphisms in Coagulant and Inflammatory Genes Modify the Phenotype of Severe Hemophilia A and B.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1009-1009 ◽  
Author(s):  
G. Jayandharan ◽  
Mercy Devadharshini ◽  
Auro Viswabandya ◽  
Sukesh C. Nair ◽  
R.V. Shaji ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Protein C ◽  
Tumor Necrosis ◽  
Hemophilia A ◽  
Tnf Alpha ◽  
Severe Hemophilia ◽  
Tgf Beta ◽  
Necrosis Factor

Abstract Among patients with severe hemophilia (<1% factor level), 10–15% are known to have a clinically mild phenotype. The basis for this phenomenon is unclear. We hypothesized that functionally significant polymorphisms in the coagulant, inflammatory and immunoregulatory genes may affect the phenotype of severe hemophilia. A total 114 patients with hemophilia A (n=95) and hemophilia B (n=19) were studied. All these patients were on minimal on-demand treatment. Patients were evaluated for the frequency and site of hemorrhage. Their clinical and radiological joint scores were documented. They were categorized as ‘mild’ (<1 affected joint and < 5 bleeds in the preceding year, n=15) or ‘severe’ (>1 affected joint and >5bleeds, n=99). Functional polymorphisms in the coagulant system (human platelet alloantigen; tissue factor; fibrinogen; factors II; V; VII; XIIIA; thrombin activable fibrinolysis inhibitor (TAFI); endothelial protein C receptor; endothelial nitric oxide synthase 3; tissue plasminogen activator; plasminogen activator inhibitor; tissue factor pathway inhibitor; protein C and S; thrombomodulin), known procoagulant factors (methylene tetrahydrofolate reductase gene), inflammatory cytokine genes (tumor necrosis factor alpha; transforming growth factor beta; interleukin (IL) 10; IL 6; IL 1beta; IL 1 beta receptor antagonist; tumor necrosis factor beta), immunoregulatory cytokine genes (interferon gamma; HLA B27; FC gamma receptor), MDM2, angiotensin converting enzyme and HFE genes were genotyped. The mean age in the two groups was 18.5 & 14.85, p=0.124. The clinical features showing significant difference are shown in the table. Of the polymorphisms studied, the FVII RQ/QQ (lower levels) (RR-3.99, p=0.022, 95% CI 1.2–13.4), TNF alpha-308AA/AG (pro-inflammatory) (RR-3.4, p=0.037, 95% CI, 1.07–10.7), TGF beta Codon 10 CC/CT (pro-inflammatory) (RR-2.8, p=0.07, 95% CI, 0.91–8.3), have been associated with a severe phenotype while MDM2GG (anti-inflammatory, RR-0.3, p=0.038, 95% CI, 0.1–0.93) was associated with a milder phenotype. We hypothesize that the bleeding frequency in severe hemophilia may be increased due to relatively lower FVII levels and a combination of cytokine driven pro-inflammatory state involving TNF alpha, TGF beta and MDM2 would cause destruction of the cartilage resulting in elaboration of metalloproteinases from chondrocytes leading to the development of arthropathy. Parameter Severe, n=99 Median (Range) Mild, n=15 Median (Range) p Value Number of bleeds /yr 15(3–74) 2(0–5) 0.000 Number of joints /yr 3 (1–6) 1 (0–1) 0.000 Age at first clinical symptom (months) 21(1–300) 60(6–90) 0.056 WFH clinical score 10 (0–27) 4 (0–21) 0.000 Pettersson score 13 (0–57) 6 (0–20) 0.001

scholarly journals Potentiation of early hematopoiesis by tumor necrosis factor-alpha is followed by inhibition of granulopoietic differentiation and proliferation

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 635-644 ◽  
Author(s):  
C Caux ◽  
C Favre ◽  
S Saeland ◽  
V Duvert ◽  
I Durand ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Inhibitory Effects ◽  
Granulocytic Differentiation ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Differentiation And Proliferation ◽  
Necrosis Factor

We have previously shown that tumor necrosis factor-alpha (TNF alpha) strongly potentiates interleukin-3 (IL-3)-induced short-term proliferation of human CD34+ hematopoietic progenitor cells (HPC). Using longer term cultures of CD34+ HPC, we demonstrate here that this initial potentiation ceases after 10 to 12 days; whereupon TNF alpha displays inhibitory effects. Thus, TNF alpha was found to inhibit cells of granulocytic affiliation while it potentiates the development of maturing cells of the monocytic lineage both in liquid and semi-solid (day 14 colony-forming unit) cultures. TNF alpha was demonstrated to reversibly block granulocytic differentiation at the level of uncommitted CD13-, CD15- blast cells that accumulate in IL-3 + TNF alpha cultures. Furthermore, growth of committed granulocytes (CD15+) from IL-3 cultures was also inhibited by TNF alpha through an arrest of cell cycle in G0/G1. Finally, the use of neutralizing anti-TNF alpha monoclonal antibody and limiting dilution studies indicate that the inhibitory effects of TNF alpha are direct. Taken together, our data demonstrate that, following a phase of potentiation of proliferation of early HPC, TNF alpha displays direct inhibitory effects due to negative interference with both granulocytic differentiation and proliferation of granulocytic cells.

scholarly journals Cardiotrophin-1 Induces Tumor Necrosis Factor Synthesis in Human Peripheral Blood Mononuclear Cells

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Michael Fritzenwanger ◽  
Katharina Meusel ◽  
Christian Jung ◽  
Marcus Franz ◽  
Zhenhua Wang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Peripheral Blood ◽  
Tumor Necrosis ◽  
Intracellular Transport ◽  
Mononuclear Cells ◽  
Elevated Serum ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Mrna Induction ◽  
Necrosis Factor

Chronic heart failure (CHF) is associated with elevated concentrations of tumor necrosis factor (TNF) and cardiotrophin-1 (CT-1) and altered peripheral blood mononuclear cell (PBMC) function. Therefore, we tested whether CT-1 induces TNF in PBMC of healthy volunteers. CT-1 induced in PBMC TNF protein in the supernatant and TNF mRNA in a concentration- and time-dependent manner determined by ELISA and real-time PCR, respectively. Maximal TNF protein was achieved with 100 ng/mL CT-1 after 3–6 hours and maximal TNF mRNA induction after 1 hour. ELISA data were confirmed using immunofluorescent flow cytometry. Inhibitor studies with actinomycin D and brefeldin A showed that both protein synthesis and intracellular transport are essential for CT-1 induced TNF expression. CT-1 caused a dose dependent nuclear factor (NF) B translocation. Parthenolide inhibited both NFB translocation and TNF protein expression indicating that NFB seems to be necessary. We revealed a new mechanism for elevated serum TNF concentrations and PBMC activation in CHF besides the hypothesis of PBMC activation by bacterial translocation from the gut.

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