scholarly journals Human recombinant interferon gamma enhances neonatal polymorphonuclear leukocyte activation and movement, and increases free intracellular calcium.

1991 ◽  
Vol 173 (3) ◽  
pp. 767-770 ◽  
Author(s):  
H R Hill ◽  
N H Augustine ◽  
H S Jaffe
Keyword(s):  
Intracellular Calcium ◽  
Interferon Gamma ◽  
Messenger Rna ◽  
Intrinsic Defect ◽  
Mononuclear Leukocytes ◽  
Developmental Defect ◽  
Phagocytic Cells ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Free Intracellular Calcium

In previous studies, we have reported that after chemotactic factor stimulation, PMNs from neonates fail to undergo certain critical activation steps. Furthermore, the concentration of free intracellular calcium reached is significantly below that of PMNs from adults. Interferon-gamma (IFN-gamma) is a lymphokine that has been shown to activate phagocytic cells, and IFN-gamma messenger RNA production by neonatal mononuclear leukocytes has been reported to be depressed. In the present studies, we found that recombinant human IFN-gamma markedly enhanced the chemotactic responses of PMNs from neonates to levels that were not different from that of PMNs from adults. Furthermore, preincubation of the neonatal cells with this recombinant human lymphokine also corrected the abnormality in intracellular calcium metabolism. These results suggest that this developmental defect in phagocytic cell movement may be the result of an intrinsic defect in IFN-gamma production resulting in deficiency of this critical phagocyte-activating lymphokine.

scholarly journals Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma.

1995 ◽  
Vol 181 (1) ◽  
pp. 33-40 ◽  
Author(s):  
D Y Leung ◽  
R J Martin ◽  
S J Szefler ◽  
E R Sher ◽  
S Ying ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Affinity ◽  
Interferon Gamma ◽  
Messenger Rna ◽  
Oral Prednisone ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Cytokine Gene Expression ◽  
Ifn Gamma ◽  
Steroid Resistant

In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p < 0.01) and IL-4 mRNA (p < 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p < 0.01) and IL-5 (p < 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p < 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

1990 ◽  
Vol 8 (6) ◽  
pp. 1070-1082 ◽  
Author(s):  
J M Kirkwood ◽  
M S Ernstoff ◽  
T Trautman ◽  
G Hebert ◽  
Y Nishida ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Dose Response ◽  
Dose Range ◽  
Cell Subset ◽  
Optimal Dosage ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Wide Range

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

scholarly journals Interferon-gamma gene expression in unstimulated bone marrow mononuclear cells predicts a good response to cyclosporine therapy in aplastic anemia

Blood ◽  
1992 ◽  
Vol 79 (10) ◽  
pp. 2532-2535 ◽  
Author(s):  
S Nakao ◽  
M Yamaguchi ◽  
S Shiobara ◽  
T Yokoi ◽  
T Miyawaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Aplastic Anemia ◽  
Interferon Gamma ◽  
Messenger Rna ◽  
Mononuclear Cells ◽  
Bone Marrow Mononuclear Cells ◽  
Ifn Gamma ◽  
Exact Test ◽  
Transfusion Independence

Cyclosporine (CyA) therapy has been shown to be effective in some patients with aplastic anemia. In an attempt to characterize aplastic patients likely to benefit from CyA therapy, we examined bone marrow mononuclear cells (BMMC) obtained before therapy from 23 patients with aplastic anemia, who were treated with CyA alone. Expression of four myelosuppressive cytokines, including tumor necrosis factor (TNF), lymphotoxin, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and interferon-gamma (IFN-gamma) was examined using polymerase chain reaction (PCR)-assisted messenger RNA (mRNA) amplification. mRNA for TNF, lymphotoxin, and MIP-1 alpha was readily detectable at variable levels in BMMC from normal and transfused controls as well as in BMMC from aplastic patients. In contrast, IFN-gamma mRNA was only demonstrable in BMMC from some patients with aplastic anemia, irrespective of a history of transfusions. Of 13 patients who responded to CyA therapy and achieved transfusion-independence, IFN-gamma mRNA was detected in 12 patients, whereas the mRNA was only detectable in 3 of 10 patients refractory to CyA therapy (P = .003, Fisher's exact test). Follow-up examination of BMMC obtained from seven CyA-responding patients after hematologic remission showed disappearance of IFN-gamma mRNA in four patients. These results suggest that detection of IFN- gamma gene expression in pretreatment BMMC from aplastic patients using PCR may be helpful in predicting a good response to CyA therapy.

scholarly journals Synergistic effect of recombinant interferon-gamma and interleukin-3 on the growth of immature human hematopoietic progenitors

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2118-2121 ◽  
Author(s):  
Y Kawano ◽  
Y Takaue ◽  
A Hirao ◽  
T Abe ◽  
S Saito ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Inhibitory Effect ◽  
Human Interferon ◽  
Dependent Manner ◽  
Hematopoietic Progenitors ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Interleukin 3 ◽  
Liquid Suspension ◽  
Colony Number

Abstract Purified peripheral blood hematopoietic progenitors from children in early remission from cancer respond to recombinant human interleukin-3 (IL-3), but not to granulocyte colony-stimulating factor (G-CSF). With these purified cells as a target, we studied the effect of recombinant human interferon-gamma (IFN-gamma) on progenitor growth, using both liquid-suspension limiting dilution assay (LDA) and regular methylcellulose culture of progenitors. We found that in LDA with IL-3, IFN-gamma directly stimulated the growth of blood progenitors in a dose- dependent manner with single-hit kinetics, whereas IFN-gamma suppressed the growth of G-CSF-supported progenitors obtained from bone marrow. The stimulatory effect was also observed in methylcellulose culture, but the addition of antibodies for G-CSF, granulocyte-macrophage CSF, IL-1 alpha, IL-1 beta, IL-6, or tumor necrosis factor did not result in a decrease of the colony number, supporting further the possible direct effect of IFN-gamma on progenitor growth. These results suggest that the inhibitory effect of IFN-gamma on hematopoietic progenitors is limited to those in an advanced stage of maturation. IFN-gamma may be one of the essential lymphokines upregulating the growth of human hematopoietic progenitor cells.

scholarly journals Biological and antigenic similarities of murine interferon-gamma and macrophage-activating factor.

1984 ◽  
Vol 159 (3) ◽  
pp. 812-827 ◽  
Author(s):  
L P Svedersky ◽  
C V Benton ◽  
W H Berger ◽  
E Rinderknecht ◽  
R N Harkins ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Interferon Gamma ◽  
T Lymphocyte ◽  
Concanavalin A ◽  
Macrophage Activation ◽  
Interleukin 2 ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Activation Factor ◽  
Species Specific

Murine peritoneal exudate cells (PEC) treated with murine recombinant interferon-gamma (IFN-gamma) (greater than 99% estimated purity), or concanavalin A-stimulated spleen cell supernatants developed tumoricidal properties (macrophage activation factor [MAF] activity). MAF activity was found to occur with treatments of 10 U/ml IFN-gamma, and at levels as low as 1 U/ml IFN-gamma if a second signal (5 ng/ml endotoxin) was present in the MAF assay. Endotoxin (lipopolysaccharide [LPS]) alone at these levels failed to induce MAF; induction of MAF was observed at 1,000-fold greater levels. The ability of IFN-gamma to stimulate murine PEC was species specific. Various sources of materials that displayed MAF activity, including supernatants from interleukin 2-dependent cloned cytotoxic murine T lymphocyte lines that did not display detectable antiviral activity, were neutralized by antibody raised and affinity purified against recombinant IFN-gamma. Thus, IFN-gamma, although never detectable by antiviral assays, appears to be present in many lymphokine preparations and has potent macrophage activation capability.

scholarly journals Induction of proliferation of B prolymphocytic leukemia cells by phorbol ester and native or recombinant interferon-gamma

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 670-675
Author(s):  
RW Sauerwein ◽  
WG van der Meer ◽  
LA Aarden
Keyword(s):  
B Cells ◽  
Conditioned Medium ◽  
Interferon Gamma ◽  
Phorbol Ester ◽  
Interleukin 2 ◽  
Gel Filtration ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Prolymphocytic Leukemia ◽  
Human B Cells

Phorbol ester phorbol myristate acetate (PMA) induces proliferation in nonmalignant human B cells and B cells from a patient with B prolymphocytic leukemia (B-PLL). Mitogen-free T cell-derived conditioned medium acts synergistically with PMA in inducing proliferation of B-PLL cells but does not enhance the PMA-stimulated outgrowth of nonmalignant B cells. Interleukin 2 (IL-2) has no effect on the outgrowth of B-PLL cells, and monoclonal antibodies against the IL-2 receptor do not influence the response to PMA and conditioned medium. Recombinant interferon-gamma (IFN-gamma), in contrast, is a potent enhancer of PMA-induced proliferation of B-PLL cells. With gel filtration techniques and with the use of anti-IFN-gamma antibodies, it is shown that IFN-gamma in the conditioned medium is responsible for the observed increase in B-PLL cell proliferation. Preincubation of B- PLL cells with IFN-gamma induces responsiveness to PMA, whereas IFN- gamma alone had no effect on these cells when pretreated with PMA. The combined data show that, in the presence of PMA, native and recombinant IFN-gamma are growth factors for B cells from a B-PLL patient and that IL-2 is not involved in this process.

Synergistic effect of recombinant interferon-gamma and interleukin-3 on the growth of immature human hematopoietic progenitors

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2118-2121 ◽  
Author(s):  
Y Kawano ◽  
Y Takaue ◽  
A Hirao ◽  
T Abe ◽  
S Saito ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Inhibitory Effect ◽  
Human Interferon ◽  
Dependent Manner ◽  
Hematopoietic Progenitors ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Interleukin 3 ◽  
Liquid Suspension ◽  
Colony Number

Purified peripheral blood hematopoietic progenitors from children in early remission from cancer respond to recombinant human interleukin-3 (IL-3), but not to granulocyte colony-stimulating factor (G-CSF). With these purified cells as a target, we studied the effect of recombinant human interferon-gamma (IFN-gamma) on progenitor growth, using both liquid-suspension limiting dilution assay (LDA) and regular methylcellulose culture of progenitors. We found that in LDA with IL-3, IFN-gamma directly stimulated the growth of blood progenitors in a dose- dependent manner with single-hit kinetics, whereas IFN-gamma suppressed the growth of G-CSF-supported progenitors obtained from bone marrow. The stimulatory effect was also observed in methylcellulose culture, but the addition of antibodies for G-CSF, granulocyte-macrophage CSF, IL-1 alpha, IL-1 beta, IL-6, or tumor necrosis factor did not result in a decrease of the colony number, supporting further the possible direct effect of IFN-gamma on progenitor growth. These results suggest that the inhibitory effect of IFN-gamma on hematopoietic progenitors is limited to those in an advanced stage of maturation. IFN-gamma may be one of the essential lymphokines upregulating the growth of human hematopoietic progenitor cells.

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

1990 ◽  
Vol 8 (7) ◽  
pp. 1269-1276 ◽  
Author(s):  
B G Redman ◽  
L Flaherty ◽  
T H Chou ◽  
A al-Katib ◽  
M Kraut ◽  
...  
Keyword(s):  
Phase I ◽  
Interferon Gamma ◽  
Phase I Trial ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Lak Cell ◽  
Recombinant Interleukin 2 ◽  
Lak Cell Activity

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

Nongenomic effects of aldosterone on intracellular calcium in porcine endothelial cells

1997 ◽  
Vol 272 (4) ◽  
pp. E616-E620 ◽  
Author(s):  
M. Schneider ◽  
A. Ulsenheimer ◽  
M. Christ ◽  
M. Wehling
Keyword(s):  
Endothelial Cells ◽  
Intracellular Calcium ◽  
Cardiovascular Effects ◽  
Mononuclear Leukocytes ◽  
Free Intracellular Calcium ◽  
In Vitro Effects ◽  
Nongenomic Effects ◽  
Porcine Endothelial Cells

Rapid in vitro effects of aldosterone on intracellular electrolytes, cell volume, and the sodium-proton antiport have been described in human mononuclear leukocytes and vascular smooth muscle cells. In the present study, we demonstrate rapid aldosterone effects on free intracellular calcium as determined by fura 2 fluorometry in single porcine endothelial cells. After addition of 100 nmol/l aldosterone, cells respond with a sustained rise in free intracellular calcium by approximately 50% of initial levels within 1-5 min. Elevations are predominantly seen in the subplasmalemmal space. Effective half-maximal concentration values for aldosterone are approximately 1 pmol/l and for cortisol approximately 1 nmol/l. These effects are blunted in calcium-free medium and absent after pretreatment by thapsigargine. They remain unchanged by a >1,000-fold excess of spironolactone. These findings indicate the existence of a nongenomic pathway for aldosterone action in porcine endothelial cells and may be related to known rapid cardiovascular effects of aldosterone in vivo mediated through the baroreceptor reflex.

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