The biology of murine eosinophil differentiation factor (an overview).
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Animals↗
Biomedical subjects
D J Warren
Publications and source records attributed to D J Warren.
Acute renal failure: diagnosis of cause needed within hours.
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Acute Kidney Injury↗
Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice.
The human bladder carcinoma cell line 5637 produces hematopoietic growth factors [granulocyte and granulocyte/macrophage colony-stimulating factors (G-CSF and GM-CSF)] and hemopoietin 1, which synergizes with CSFs to stimulate colony formation by primitive hematopoietic stem cells in 5-fluorouracil-treated mouse bone marrow. Molecular and functional properties of hemopoietin 1 identified it as identical to interleukin 1 alpha (IL-1 alpha). When bone marrow cells from 5-fluorouracil-treated mice were cultured in suspension for 7 days with recombinant human IL-1 alpha and/or G-CSF, it was found that the two factors synergized to enhance recovery of myelopoietic cells and colony-forming cells of both high and low proliferative potential. G-CSF alone did not sustain these populations, but the combination had greater-than-additive stimulating capacity. In vivo, 5-fluorouracil (150 mg/kg) produced profound myelosuppression and delayed neutrophil regeneration for up to 2 weeks in C3H/HeJ mice. Daily administration of recombinant human G-CSF or recombinant human IL-1 alpha accelerated recovery of stem cells, progenitor cells, and blood neutrophils by up to 4 days in 5-fluorouracil-treated C3H/HeJ and B6D2F1 mice. The combination of IL-1 alpha and G-CSF acted synergistically, reducing neutropenia and accelerating recovery of normal neutrophil numbers by up to 7 days. This was accompanied by accelerated regeneration of spleen colony-forming units and erythroid, myeloid, and megakaryocytic progenitor cells in marrow and spleen, with enhanced erythroid and granulocytic differentiation. These results indicate the possible therapeutic potential of combination therapy with IL-1 and hematopoietic growth factors such as G-CSF in the treatment of chemotherapy- or radiation-induced myelosuppression.
Animals↗
Effects of cyclosporine on responses of murine B cells to T cell-derived lymphokines.
Cyclosporine (CS) inhibits the stimulation of both T and B lymphocytes by certain agents, but not by others. Here we have studied the effects of the drug on the responses of murine B cells to T cell-derived B cell growth and differentiation factors. We show that activation of resting B cells by B cell-stimulatory factor-1 (BSF-1) is resistant to CS, whereas stimulation by anti-Ig antibodies is not, which is in agreement with earlier findings. Furthermore, B cell proliferation elicited by co-stimulation with anti-Ig plus BSF-1 remains drug susceptible. In contrast, the stimulation of large (presumably preactivated) B cells by B cell growth factor II to synthesize DNA or to secrete Ig is inhibited by low concentrations of CS. These results therefore contrast with earlier findings with human B cells, and with those using T cells from various species, which showed that the responses of preactivated cells to growth factors are resistant to the drug. It thus appears that in the mouse CS can affect all stages of B cell stimulation.
Animals↗
Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells.
A purified murine lymphokine, eosinophil differentiation factor (EDF), was found to be a selective stimulus for the clonal proliferation and differentiation of murine eosinophil progenitor cells, establishing it as the murine eosinophil colony-stimulating factor (Eo-CSF). EDF was also active on human eosinophil progenitors and mature blood eosinophils, but had no effect on neutrophil or macrophage precursor cells, nor on blood neutrophils. In culture of human bone marrow cells, EDF stimulated equal numbers and equal sizes of eosinophil colonies to develop when compared with human placental conditioned medium, a source of human CSFs, suggesting that all responsive progenitor cells were stimulated. Clone transfer experiments and the linear relationship between number of bone marrow cells plated and colonies produced confirmed that the action of EDF was directly on eosinophil progenitor cells. EDF increased the capacity of human blood eosinophils, but not neutrophils, to kill antibody-coated tumor cells and to phagocytose serum-opsonized yeast cells. This functional activation was associated with the enhanced expression of functional antigens (GFA-1, GFA-2, and the receptor for C3bi) on eosinophils. The possession by EDF (Eo-CSF) of all the properties expected of a human eosinophil CSF raises the possibility that a human analog of this molecule exists, and is involved in the regulation of production and function of human eosinophils in vivo.
Animals↗
Interleukin-4 (B cell growth factor-II/eosinophil differentiation factor) is a mitogen and differentiation factor for preactivated murine B lymphocytes.
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Animals↗
Interleukin 4 (B-cell growth factor II/eosinophil differentiation factor) is a mitogen and differentiation factor for preactivated murine B lymphocytes.
Recently we described a murine T-cell hybrid that produces activities that promote the differentiation of eosinophils (eosinophil differentiation factor) and cause proliferation of the BCL1 B-cell lymphoma (B-cell growth factor II activity). Both activities appear to be associated with the same molecule, which has therefore been termed interleukin 4. The hybrid does not produce any other known lymphokines. We now find that purified interleukin 4 has no effects on small resting B cells but induces naturally occurring large B cells (which have presumably been preactivated in vivo) to synthesize DNA and to secrete IgM and low levels of IgG. B cells activated by anti-Ig antibodies apparently only become responsive to the factor once they have reached late G1 stage. All bioactivities of interleukin 4 are associated with a protein of Mr 44,000 (by NaDodSO4/PAGE). Therefore these results demonstrate that this lymphokine alone is sufficient to induce clonal expansion and maturation of activated B cells.
Animals↗
Eosinophil differentiation factor also has B-cell growth factor activity: proposed name interleukin 4.
A mouse lymphokine that stimulates the production of functional eosinophils in liquid bone marrow cultures has recently been described [Sanderson, C.J., Warren, D.J. & Strath, M. (1985) J. Exp. Med. 162, 60-74]. This factor appears to be specific for the eosinophil lineage in hemopoietic differentiation and is analogous to colony-stimulating factors described for other hemopoietic lineages. In this paper we report that this factor appears to be identical to the B-cell growth factor II described by Swain and Dutton [Swain, S.L. & Dutton, R.W. (1982) J. Exp. Med. 156, 1821-1834]. This conclusion is based on the coordinate expression of the two activities by a panel of alloreactive T-cell clones and lines and on copurification through a series of protein separation techniques. The reason for a single lymphokine's having these widely differing biological activities is unclear, and its duality presents problems in using terminology based on either assay system. For this reason we propose the name "interleukin 4" for this molecule, and we suggest the defining property should be its eosinophil-differentiating activity.
Animals↗
Comparison of the effects of atenolol, sotalol and labetalol on muscle blood flow in man.
A double-blind study of the effect of three beta-adrenoceptor blocking drugs (beta-blockers) on exercise muscle blood flow (MBF) in 14 normotensive volunteers was carried out. MBF was measured by the xenon-133 clearance technique. MBF was not altered by placebo, sotalol or labetalol. Atenolol significantly reduced MBF compared with placebo, sotalol and labetalol. We conclude that sotalol and labetalol may be more useful than conventional beta-blockers for treatment of hypertension or angina in association with peripheral vascular disease.
Adrenergic beta-Antagonists↗
Purified colony-stimulating factors enhance the survival of human neutrophils and eosinophils in vitro: a rapid and sensitive microassay for colony-stimulating factors.
The survival of purified human blood neutrophils and eosinophils was monitored using microwell cultures. Survival was enhanced in cultures containing human or murine colony-stimulating factors (CSFs). The survival of both cell types was enhanced by purified recombinant human granulocyte-macrophage CSF and partially purified preparations of the native molecule, CSF alpha. Neutrophil but not eosinophil survival was enhanced by murine granulocyte-CSF and its human analogue CSF beta. Eosinophil but not neutrophil survival was enhanced by murine eosinophil differentiation factor (eosinophil CSF). The mature cell survival provided an assay system for CSF that was 10(2) to 10(3) more sensitive than the standard assay of stimulation of colony formation in agar cultures and could be completed within 48 hours. These results demonstrated that CSF induced and enhanced survival of mature human neutrophils and eosinophils in vitro. Furthermore, the lineage specificity of purified murine CSFs was retained in their action on human cells.
Animals↗
Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors.
A colorimetric assay for peroxidase has been applied to the detection of eosinophils in bone marrow cultures and tissue cell suspensions. The substrate solution consists of 0.1 mM o-phenylenediamine in 0.05 M Tris-HCl buffer pH 8.0 containing 0.1% Triton and 1 mM hydrogen peroxide. The method is shown to be an easy and reproducible method of detecting eosinophils, with insignificant interference from neutrophils.
Amitrole↗
Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures.
Factors stimulating eosinophil differentiation in vitro have been studied by means of a liquid bone marrow culture system in which the number of eosinophils is estimated directly by morphology or indirectly by assay for eosinophil peroxidase. The results show that eosinophil colonies are not formed in agar, emphasizing the importance of the liquid culture system. Three types of evidence identify a novel lymphokine, eosinophil-differentiating factor (EDF). (a) Coordinate analysis of lymphokine activity in media conditioned by a panel of parasite antigen and another panel of alloantigen-reactive T cell clones indicates that EDF is distinct from interleukin 2 (IL-2), IL-3, and bone marrow proliferation activity (BMPA). (b) A T hybrid (NIMP-TH1) produces EDF but no IL-2, IL-3, interferon, or colony-stimulating factor. (c) Gel filtration of conditioned media (CM) indicates that NIMP-TH1 and a T clone (NIMP-T2) produce EDF (Mr 46,000). NIMP-T2 also produced IL-3 (Mr 26,000) but this was easily separated from EDF. IL-3 is also shown to have eosinophil differentiation activity (EDA) but this represents a very small proportion of the EDA in T2-CM. Fractionation of WEHI-3-CM indicates that EDA from this source has a similar elution profile to IL-3 (Mr 35-36,000). Furthermore, a comparison of the relative activities in purified IL-3 and WEHI-3-CM indicates that all the EDA can be attributed to the IL-3 in the latter. EDF is shown to stimulate production of eosinophils in long-term bone marrow cultures; the kinetics of eosinophil production suggests that EDF is acting on committed precursors in the bone marrow. The transient nature of eosinophil production suggests that precursors from multipotential stem cells are not produced. The eosinophils produced in these cultures are morphologically normal and functional in that they lysed sheep red blood cells coated with IgG1, IgG2a, and IgG2b, but not with IgM, IgA, or IgE. In addition, they were capable of adhering to and killing Schistosoma mansoni schistosomula.
Animals↗
A comparison of the effects of intravenous propranolol and nadolol on the renal response to hypertonic saline infusion.
Intravenous loading with 500 ml of 2.7% saline increased the clearance of PAH and inulin and urine sodium excretion in 14 healthy subjects. Intravenous propranolol (0.075 and 0.15 mg/kg) did not alter PAH or inulin clearance at rest but abolished the increase expected during saline infusion. There was no consistent effect on urinary sodium excretion. Intravenous nadolol (0.05 and 0.75 mg/kg) reduced resting PAH and inulin clearances by up to 25%. Both clearances fell significantly during saline infusion but natriuresis was not significantly reduced in spite of the changes in renal function. There was no evidence from these studies in normal volunteers that nadolol confers any advantages over propranolol in its effects on renal function.
Adrenergic beta-Antagonists↗
Effect of haemodialysis on the control of the circulation in patients with chronic renal failure.
The mechanisms of hypotension during haemodialysis were investigated by studying cardiovascular reflexes, body fluid volumes, and osmolality in 11 patients with renal failure before and after haemodialysis and in 17 normal subjects before and after furosemide diuresis. Blood pressure and heart rate responses to tests of autonomic nervous function were unaffected in either group except that in the patients, head-up tilt after haemodialysis caused a fall in blood pressure. This was associated with a greater fall in cardiac output than before haemodialysis but with a similar rise in peripheral vascular resistance. Resting plasma noradrenaline levels were higher than normal, and the rise in plasma noradrenaline levels in response to tilt was unaffected by haemodialysis. Plasma renin activity rose in response to head-up tilt in normal subjects, but not in patients either before or after haemodialysis. Our studies indicate that changes in plasma potassium and osmolality or the possible peripheral circulatory effects of acetate do not impair the regulation of the circulation in response to haemodialysis. Haemodialysis does not reduce plasma noradrenaline levels. Impaired myocardial function in response to fluid depletion or unresponsiveness of the renin-angiotensin system may contribute to haemodialysis hypotension.
Adult↗
The effect of age on the cardiovascular responses to isometric exercise: a test of autonomic function.
Isometric exercise, promulgated as a test of autonomic function, has not been investigated in the elderly. Increasing age does not affect the cardiovascular responses to isometric exercise. Variability studies during fatiguing isometric exercise confirm that it is a valuable test of autonomic function in the elderly.
Adult↗
Production of a T-cell hybrid producing a lymphokine stimulating eosinophil differentiation.
Spleen cells from mice undergoing a parasite-induced eosinophilia were fused with an azaguanine-resistant subline of the thymoma BW5147. A stable T hybrid (NIMP-TH1) was isolated and selected by recloning repeatedly by limiting dilution. The hybrid nature of NIMP-TH1 was confirmed by its expression of both parental alleles of Thy-1 and by chromosome analysis (modal chromosome number 102). On stimulation with phorbol myristate acetate, this hybrid releases a soluble activity which acts as a stimulator of eosinophil differentiation in vitro. Addition of hybrid conditioned medium to bone marrow cultures results in a selective stimulation of eosinophil production with no detectable increase in neutrophil or macrophage differentiation. The lymphokines interleukin-2 (IL-2) and interferon (IFN) are undetectable in NIMP-TH1 conditioned media. Although at high concentrations NIMP-TH1 supernatants are able to support very low levels of DNA synthesis in an IL-3-dependent cell line, and IL-3 appears to support low levels of eosinophil differentiation, dose-response curves show that the factor produced by NIMP-TH1 can be clearly segregated from IL-3 by its marked specificity for cells belonging to the eosinophil lineage. The factor present in these supernatants has been provisionally termed eosinophil differentiation factor (EDF).
Animals↗
The effect of captopril on autonomic reflexes in human hypertension.
The effects of acute administration of captopril on heart rate, blood pressure and physiological responses to head-up tilt, hand-grip, exercise and Valsalva manoeuvre were studied in 25 hypertensive subjects (10 untreated, 15 previously treated). After chronic administration for 8-12 weeks the effect on heart rate, blood pressure and the response to head-up tilt were studied again in 15 of these subjects. After the first dose of captopril (0.5 mg/kg), both systolic and diastolic blood pressures fell significantly, with no change in heart rate. Head-up tilting produced a significant increase in heart rate without any alteration in the blood pressure; hand-grip produced a significant increase in heart rate and blood pressure. These responses and exercise-induced tachycardia were unaltered by captopril. There was a significant reduction in the Valsalva ratio. After chronic administration the hypotensive efficacy was maintained for 10-12 h after the last dose, suggesting that twice daily dosage may be sufficient. There was a significant reduction in the basal supine heart rate by captopril. Head-up tilt produced the same physiological changes as in the acute study. These findings suggest that captopril has a vagotonic effect, possibly associated with resetting of baroceptor mechanisms. This could be one explanation for the hypotensive effect of captopril even in low-renin states.
Autonomic Nervous System↗
The production of lymphokines by primary alloreactive T-cell clones: a co-ordinate analysis of 233 clones in seven lymphokine assays.
A total of 233 primary alloreactive T-cell clones have been tested for the production of interleukin-2 (IL-2), interleukin-3 (IL-3), immune(gamma) interferon (IFN) and granulocyte-macrophage colony-stimulating factor (CSF-2), B-cell growth factor I and II (BCGFI, BCGFII), and eosinophil differentiation factor (EDF). EDF was assayed by means of the eosinophil differentiation assay (EDA). Two principal correlations were observed: IL-3 was shown to be the major lymphokine detected in the bone marrow proliferation assay (BMPA) used to detect CSF-2, and there was a high correlation between the EDA and BCGFII. Subsequent work has suggested that this latter correlation is because a single factor is responsible for both activities. Apart from these two exceptions, and low level correlations probably due to the fact that different assays detect more than one lymphokine, there was no evidence for co-ordinate expression of lymphokines. There was a large variation in amounts of individual lymphokines produced. More clones produced multiple lymphokines than would be expected from independent control. Taken together, this pattern of regulation is consistent with the hypothesis that antigen stimulation of T cells results in the activation of all the lymphokine genes, but the amount of each produced is determined by secondary controlling mechanisms.
Animals↗