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.

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 Bidirectional effects of transforming growth factor beta (TGF-beta) on colony-stimulating factor-induced human myelopoiesis in vitro: differential effects of distinct TGF-beta isoforms

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2239-2247 ◽  
Author(s):  
SE Jacobsen ◽  
JR Keller ◽  
FW Ruscetti ◽  
P Kondaiah ◽  
AB Roberts ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Hematopoietic Progenitor Cells ◽  
Colony Stimulating Factor ◽  
Tgf Beta ◽  
Hematopoietic Progenitor ◽  
Growth Factor Beta ◽  
Beta 2 ◽  
Macrophage Colony ◽  
Stimulating Factor

Transforming growth factor-beta (TGF-beta) has potent antiproliferative effects on human hematopoietic progenitor cells. We report here that TGF-beta 1 and -beta 2 also exert bimodal dose-dependent stimulation of granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte- CSF-induced day 7 granulocyte-macrophage colony-forming units. This increase in colony formation was restricted to low doses (0.01 to 1.0 ng/mL) of TGF-beta 1 and was due to increased granulopoiesis, showing that TGF-beta can affect the differentiation as well as the proliferation of hematopoietic progenitors. Furthermore, TGF-beta 3 was found to be a more potent inhibitor of hematopoietic progenitor cells than TGF-beta 1 and -beta 2. In contrast to the bidirectional proliferative effects of TGF-beta 1 and -beta 2, the effects of TGF- beta 3 on human hematopoiesis were only inhibitory, showing for the first time that TGF-beta isoforms differ not only in potencies but also with regard to the nature of the response they elicit.

scholarly journals Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor- alpha secretion

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2622-2631 ◽  
Author(s):  
N Oyaizu ◽  
TW McCloskey ◽  
S Than ◽  
R Hu ◽  
VS Kalyanaraman ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Apoptosis ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Cross Linking ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
T Cell Apoptosis ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract We have recently shown that, in unfractioned peripheral blood mononuclear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is sufficient to induce T-cell apoptosis. However, the underlying mechanism for the CD4XL-mediated T-cell apoptosis is largely unknown. Several recent studies have shown that Fas antigen (Ag), a cell-surface molecule, mediates apoptosis-triggering signals. We show here that cross-linking of CD4 molecules, induced either by anti-CD4 monoclonal antibody (MoAb) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal lymphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effects. The upregulation of Fas Ag closely correlated with apoptotic cell death, as determined by flow cytometry. In addition, CD4XL resulted in the induction of interferon-gamma (IFN- gamma) and tumor necrosis factor-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribute to Fas Ag upregulation and both anti- IFN-gamma and anti-TNF-alpha antibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apoptosis. These findings strongly suggest that aberrant cytokine secretion induced by CD4XL and consequent upregulation of Fas Ag expression might play a critical role in triggering peripheral T-cell apoptosis and thereby contribute to HIV disease pathogenesis.

scholarly journals Ability of flt3 ligand to stimulate the in vitro growth of primitive murine hematopoietic progenitors is potently and directly inhibited by transforming growth factor-beta and tumor necrosis factor-alpha

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5016-5026 ◽  
Author(s):  
SE Jacobsen ◽  
OP Veiby ◽  
J Myklebust ◽  
C Okkenhaug ◽  
SD Lyman
Keyword(s):  
Cell Growth ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Tgf Beta ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Growth Factor Beta ◽  
Necrosis Factor

The recently cloned flt3 ligand (FL) stimulates the growth of primitive hematopoietic progenitor cells through synergistic interactions with multiple other cytokines. The present study is the first demonstrating cytokines capable of inhibiting FL-stimulated hematopoietic cell growth. Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta l) potently inhibited the clonal growth of murine Lin-Sca-l+ bone marrow progenitors stimulated by FL alone or in combination with granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), interleukin (IL)-3, IL-6, IL-11, or IL-12. TGF-beta 1 inhibited more than 96% of the myeloid colony formation in response to these cytokine combinations, whereas TNF-alpha reduced the number of colonies by 58% to 96% depending on the cytokine by which FL was combined. In addition, both TNF-alpha and TGF-beta 1 inhibited more than 90% of B220+ cell production from B220- bone marrow cells stimulated by FL + IL-7. The effects of TNF-alpha and TGF-beta 1 appeared to be due to a direct effect and on the early progenitors because the inhibition was observed at the single cell level, and because delayed addition of the two inhibitors for only 48 hours dramatically reduced their inhibitory effects. A neutralizing anti-TGF- beta antibody showed the presence of endogenous TGF-beta in the cultures and potently enhanced the ability of FL to stimulate progenitor cell growth in the absence of other cytokines. Agonistic antibodies specifically activating the p75 TNF receptors were more efficient than wild type murine TNF-alpha in signaling growth inhibition of Lin-Sca-l+ progenitor cells, whereas the p55 agonist had less effect than murine TNF-alpha. Finally, TGF-beta increased the number of FL + IL-11-stimulated Lin-Sca-1+ cells in the G1 phase of the cell cycle with 76%, whereas TNF-alpha only had a marginal effect on cell cycle distribution. Thus, TGF-beta, TNF-alpha, and p75 TNF receptor agonists are potent direct inhibitors of FL-stimulated progenitor cell growth in vitro.

scholarly journals Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor cells

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2376-2385 ◽  
Author(s):  
C Caux ◽  
B Vanbervliet ◽  
C Massacrier ◽  
I Durand ◽  
J Banchereau
Keyword(s):  
Tumor Necrosis Factor ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Langerhans Cells ◽  
Tumor Necrosis ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Cord Blood Cd34 ◽  
Necrosis Factor

We have previously shown that tumor necrosis factor (TNF)alpha strongly potentiates the granulocyte-macrophage colony-stimulating factor (GM- CSF)/interleukin (IL)-3-dependent proliferation of CD34+ hematopoietic progenitor cells (HPC) through the recruitment of early progenitors with high proliferative potential. Furthermore, the combination of GM- CSF and TNFalpha allows the generation of large numbers of dendritic/Langerhans cells (D-Lc). Herein, we analyzed whether IL-3, when combined to TNFalpha would, as does GM-CSF, allow the generation of CD1a+ D-Lc. Accordingly, cultures of cord blood CD34+ HPC with IL-3 + TNFalpha yielded 20% to 60% CD14+ cells and 11% to 17% CD1a+ cells, while IL-3 alone did not generate significant numbers of CD1a+ cells. Although the percentage of CD1a+ cells detected in IL3 + TNFalpha was lower than that observed in GM-CSF + TNFalpha (42% to 78%), the strong growth induced by IL-3 + TNFalpha generated as many CD1a+ cells as did GM-CSF + TNFalpha. The CD14+ and CD1a+ cells generated with IL-3 + TNFalpha are similar to CD14+ and CD1a+ cells generated in GM-CSF alone and GM-CSF + TNFalpha, respectively. CD1a+ cells differed from CD14+ cells by (1) dendritic morphology, (2) higher expression of CD1a, CD1c, CD4, CD40, adhesion molecules (CD11c, CD54, CD58), major histocompatibility complex (MHC) class II molecules and CD28 ligands (CD80 and CD86), (3) lack of Fc receptor FcgammaRI (CD64) and complement receptor CR1 (CD35) expression, and (4) stronger induction of allogeneic T-cell proliferation. Thus, in combination with TNFalpha, IL-3 is as potent as GM-CSF for the generation of CD1a+ D-Lc from cord blood CD34+ HPC. The dendritic cell inducing ability of IL-3 may explain why mice with inactivated GM-CSF gene display dendritic cells.

Tumor necrosis factor-alpha and interferon-gamma reduce prolactin release in vitro

1990 ◽  
Vol 259 (5) ◽  
pp. E672-E676
Author(s):  
P. E. Walton ◽  
M. J. Cronin
Keyword(s):  
Anterior Pituitary ◽  
Tumor Necrosis ◽  
Cell Function ◽  
Tnf Alpha ◽  
Pituitary Cells ◽  
Prolactin Release ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Factor Alpha ◽  
Necrosis Factor

Prolactin binds to lymphocytes and monocytes and can modulate immune cell function. It was postulated that proteins released from activated macrophages and lymphocytes could directly influence prolactin release and thus form an endocrine control loop during infection, tumor invasion, or inflammation. This hypothesis was tested by exposing cultured rat anterior pituitary cells to murine tumor necrosis factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma) for 24 h before a 4-h test of cell function. Overall prolactin accumulation during this first 24 h was inhibited by TNF-alpha and markedly reduced by TNF-alpha plus IFN-gamma. In contrast, thyroid-stimulating hormone levels were unchanged in these same media. During the subsequent 4-h challenge, both cytokines reduced thyrotropin-releasing hormone-stimulated prolactin release but had no effect on inhibited prolactin release mediated by dopamine and somatostatin receptors. Cellular viability (assessed by trypan blue and chromium release assays) and prolactin cell content were unchanged after TNF-alpha or IFN-gamma treatment. We conclude that both TNF-alpha and IFN-gamma have the potential to act directly on anterior pituitary cells to slow the rate of prolactin release.

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

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