Autocrine interferon and the suppression of the c-myc nuclear oncogene.
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Cell Differentiation↗
Biomedical subjects
A Kimchi
Publications and source records attributed to A Kimchi.
Tumor necrosis factor reduces c-myc expression and cooperates with interferon-gamma in HeLa cells.
The suppression of the c-myc nuclear oncogene is associated with growth arrest and may therefore be directly controlled by naturally occurring growth inhibitors. The effect of tumor necrosis factor (TNF) and of interferon-gamma (IFN-gamma) on c-myc expression was investigated in HeLa cells, which respond to these cytokines by a specific arrest in the G0/G1 phase of the cell cycle. Northern blot and nuclear transcription analyses indicated that each cytokine reduced within 1 to 3 hours the c-myc messenger RNA levels as a result of transcriptional inhibition. Adding the two cytokines together at saturating levels resulted in enhanced inhibition of c-myc transcription and of the c-myc messenger RNA steady-state levels. While the reduction of c-myc messenger RNA by IFN-gamma was dependent on new protein synthesis, the inhibitory effect of TNF on c-myc messenger RNA was direct and was not abrogated by cycloheximide. The differential effect of the protein synthesis inhibitor and the cooperative inhibitory effects of the two cytokines when added together suggest that IFN-gamma and TNF reduce c-myc transcription through different molecular mechanisms.
Cell Survival↗
Autocrine beta-related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation.
Different hematopoietic cells produce minute amounts of beta-related interferon (IFN) following induction of differentiation by chemical or natural inducers. The endogenous IFN binds to type I cell surface receptors and modulates gene expression in the producer cells. We show that self-induction of two members of the IFN-induced gene family differs in the dose response sensitivity and the prolonged kinetics of mRNA accumulation from the response to exogenous IFN-beta 1. Production and response to endogenous IFN are also detected when bone marrow precursor cells differentiate to macrophages after exposure to colony stimulating factor 1. In M1 myeloid cells induced to differentiate by lung-conditioned medium, addition of antibodies against IFN-beta partially abrogates the reduction of c-myc mRNA and the loss in cell proliferative activity, which both occur during differentiation. The endogenous IFN therefore functions as an autocrine growth inhibitor that participates in controlling c-myc suppression and the specific G0/G1 arrest during terminal differentiation of hematopoietic cells.
2',5'-Oligoadenylate Synthetase↗
Left ventricular performance in septic shock: reversible segmental and global abnormalities.
Left ventricular dysfunction has been implicated in the pathogenesis of septic shock, but little is known about its natural history, cause, and prognostic significance. Left ventricular performance was assessed by serial radionuclide and hemodynamic studies in 35 patients with culture-proven septic shock. The mean age (+/- S.D.) of the group was 64 +/- 18 years; 16 of the subjects were women, and 15 had antecedent heart disease. On the first study, the left ventricular stroke work index was depressed in 33 (94%) patients, and nineteen (54%) had a left ventricular ejection fraction less than 0.48. Twenty-two (63%) of the patients had segmental and four had generalized wall motion abnormalities. Conventional hemodynamic parameters were of no value in predicting the patients who had a depressed left ventricular ejection fraction or segmental abnormalities. Patients with underlying heart disease had a much higher frequency (87%) of segmental dysfunction than those without underlying heart disease (45%; p = 0.016), but no differences were noted in the left ventricular ejection fraction or left ventricular stroke work index of these two groups. Segmental abnormalities and low ejection fractions were seen more often in patients with a large left ventricular end-diastolic volume index. Only five subjects had a systemic vascular resistance index greater than 2580 dynes X sec X cm-5 per m2, and the correlation between systemic vascular resistance index and left ventricular ejection fraction was poor. No difference was found in the mean coronary perfusion pressure of those with segmental abnormalities and those with normal wall motion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Salutary hemodynamic and sustained clinical beneficial effects of nisoldipine, a new calcium channel blocker, in patients with recurrent ischemia and severe heart failure.
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Aged↗
Reversal of rest myocardial asynergy during exercise: a radionuclide scintigraphic study.
UNLABELLED: While exercise-induced segmental left ventricular wall motion abnormalities are well described, the phenomenon of improvement in certain asynergic segments during exercise in some patients remains a curiosity. To assess this unexpected finding, results were analyzed in 85 patients with wall motion abnormalities at rest who underwent two view (45 degrees left anterior oblique and anterior) exercise radionuclide ventriculography and exercise thallium-201 myocardial perfusion imaging. Wall motion was scored with a 5 point system (from 3 [normal] to - 1 [dyskinesia]); normalization or increase of 2 or more points with exercise signified improvement. Forty-eight patients (56%) had no change or further deterioration of wall motion at peak exercise, 15 (18%) showed both improvement of wall motion and deterioration and 22 (26%) showed only improvement of wall motion. Wall motion improvement during exercise was found in 57 (20%) of 279 segments with asynergy at rest. Of these 57 segments improving with exercise, 45 (79%) showed mild and 12 (21%) showed severe asynergy at rest. Only seven segments (12%) were associated with pathologic Q waves. Thallium-201 perfusion was normal in 44 segments (77%) while only 6 segments (11%) had reversible and only 7 (12%) had nonreversible thallium-201 defects. IN CONCLUSION: 1) wall motion that is abnormal at rest can sometimes improve with exercise; 2) this phenomenon generally occurs in zones without a Q wave or nonreversible thallium-201 defect. Hence, segments with abnormal wall motion at rest that show improvement with exercise appear to represent viable nonischemic segments.
Adult↗
Inhibitory effects of interferon on the expression of genes regulated by platelet-derived growth factor.
The G0/G1 to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be specifically blocked by the administration of interferon (IFN) to the system. In the present communication, we studied whether IFN inhibits the early events in the G0/G1 phase that are initiated by the platelet-derived growth factor (PDGF). The results show that IFN inhibits most of the PDGF-mediated increase of c-myc, ornithine decarboxylase, and beta-actin mRNAs measured 3 hr after stimulation. c-fos mRNA levels are reduced by IFN as early as 20 min after exposure of the quiescent cells to PDGF. The expression of several genes that belong to the competence gene family is, therefore, inhibited by IFN and this could account for the failure of the IFN-treated cells to enter into the S phase when growth factors present in the platelet-poor plasma are added. We also report that the PDGF-mediated increase in the uptake of deoxyglucose is not impaired by IFN, thus suggesting that the early effects of IFN on gene expression do not result from inhibition of binding of PDGF to its cell-surface receptors. Unlike the direct stimulatory effect of PDGF, which is not sensitive to cycloheximide, the inhibitory effect of IFN on c-myc mRNA levels depends in part on protein synthesis. We propose that a putative product of one of the IFN-induced genes could mediate the decrease in expression of the PDGF-regulated gene family.
Animals↗
Reduction of c-myc expression by IFN: further analysis of the sensitive and the resistant phenotype of cells.
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Cell Line↗
Treadmill exercise testing in a middle-aged Jerusalem population sample. The Jerusalem Lipid Research Clinic Prevalence Study.
We studied determinants of the exercising physical capacity of 1,640 subjects (1,043 men and 597 women) using the Bruce protocol as modified by Sheffield. These participants represented a sample of parents of 17-year-old adolescents living in Jerusalem. Apparently healthy participants underwent a graded treadmill exercise test (88% of the men and 87% of the women). Exercise was terminated when the subject achieved a heart rate of 85 to 90% of the predicted maximal heart rate or could not continue for other reasons, mainly fatigue or weakness. Exercise performance was assessed according to time on the treadmill. On univariate analysis, duration of exercise was related in both sexes to age, country of origin, reported physical exercise, resting heart rate, systolic and diastolic blood pressure, body mass index and plasma lipids and lipoproteins. In multivariate analysis, time was related to age, body mass index, heart rate and habitual physical exercise in both men and women, and to systolic and diastolic blood pressure in men only. Cigarette smoking and plasma lipid levels were not independently related to time on the treadmill in either sex. Ethnic differences were observed.
Age Factors↗
Autogenous production of interferon-beta switches on HLA genes during differentiation of histiocytic lymphoma U937 cells.
The expression of class I HLA genes was measured during the in vitro differentiation of human U937 lymphoma cells towards macrophages. Following the onset of differentiation by phorbol myristate acetate the levels of cytoplasmic mRNA that hybridized with a [32P]HLA-B cDNA probe increased by a factor of nine. Elevation in HLA mRNA accumulation was followed by an increase in the rate of synthesis of HLA proteins and also by a dramatic increase in class I HLA cell surface antigen expression, as shown by cytofluorimetric analysis. The elevation in HLA mRNA and surface antigens could be prevented by adding antibodies against human interferon-beta (IFN-beta) to the culture medium at the onset of differentiation. Interferon antiviral activity was detected in the medium of differentiated U937 cells. The same anti-IFN-beta antibodies prevented the increase in (2'-5')oligo(A) synthetase activity which also takes place in differentiating U937 cells. Accumulation of the IFN-induced (2'-5')oligo(A) synthetase in U937 cells is preceded by an increase in its specific 1.6-kb mRNA as shown by hybridization to cloned (2'-5')-oligo(A) synthetase cDNA. The enzyme was preferentially found in the nuclear fraction of differentiating U937 cells. We suggest that an autogenous production of interferon-beta by the differentiating cells, switches on expression of the class I HLA genes as well as that of the (2'-5')oligo(A) synthetase.
2',5'-Oligoadenylate Synthetase↗
Right ventricular performance in septic shock: a combined radionuclide and hemodynamic study.
Twenty-five patients with septic shock underwent simultaneous radionuclide ventriculography and right heart catheterization to clarify the role of the right ventricle in this syndrome. A depressed right ventricular ejection fraction (less than 38%) was present in 13 patients and was found in patients with elevated cardiac output (4 of 6 patients) and with normal or low cardiac output (9 of 19 patients). Right ventricular dysfunction was seen with or without acute respiratory failure. In eight patients, a depressed right ventricular ejection fraction was seen in combination with an abnormal left ventricular ejection fraction (less than 48%), but in five patients, right ventricular ejection fraction impairment occurred with normal left ventricular ejection fraction. There was no significant correlation between abnormal right ventricular afterload and depressed right ventricular ejection fraction. No clinical or hemodynamic finding could be used to identify patients with diminished right ventricular ejection fraction. On follow-up study in 17 surviving patients, right ventricular ejection fraction improved in 6 and was unchanged in 11. Improvement in right ventricular ejection fraction occurred more frequently in patients without pulmonary hypertension or respiratory distress. The results suggest that right ventricular dysfunction in septic shock may be more common than previously suspected. It may be caused by abnormalities in right ventricular afterload in some patients and depressed myocardial contractility in others. The findings are of therapeutic importance since interventions that diminish right ventricular afterload and increase right ventricular contractility would be appropriate in patients with septic shock and right ventricular dysfunction.
Adult↗
High and low potency interferon-alpha subtypes induce (2'-5') oligoadenylate synthetase with similar efficiency.
Three major subtypes of human interferon-alpha (IFN-alpha), isolated from virus-induced leukocytes, were compared for their antiviral and anticellular activities on one hand, and for their ability to induce (2'-5') oligoadenylate synthetase on the other hand. One subtype, IFN-alpha 1, was found to have low specific antiviral (6.10(6)-5.10(7) units/mg) and anticellular activities when measured on a variety of human cells. A second subtype, exhibiting an unusually high molecular weight (26,000) by SDS-polyacrylamide gel electrophoresis (IFN-alpha 26K), was found to have the highest known specific antiviral (8.10(8)-2.10(9) units/mg) and anticellular activities. Thus, these two subtypes of IFN-alpha differ by a factor of 330 and represent the two extremes in the antiviral scale on human cells. A third subtype, IFN-alpha 2, was tested as well and was found to have intermediate antiviral and anticellular activities. The ability of these three subtypes to induce (2'-5') oligoadenylate synthetase in human cells was then measured. It was found that on a weight basis, the three subtypes were equally effective in inducing the enzyme. Since the level of (2'-5') adenylate oligomers is affected also by the interferon-induced (2'-5') phosphodiesterase, the ability of these subtypes to induce this enzyme was compared as well and was found to be very similar. We therefore conclude that the differences in potency between these IFN-alpha subtypes are not related to their ability to induce (2'-5') oligoadenylate synthetase.
2',5'-Oligoadenylate Synthetase↗
Reduction in p53 synthesis during differentiation of Friend-erythroleukemia cells. Correlation with the commitment to terminal cell division.
The process of cell differentiation in Friend-erythroleukemia cells was accompanied by 80-90% inhibition of p53 synthesis. This decrease was found to be linked to changes in cell-cycle distribution characteristics of the growth arrest program during differentiation rather than to the induction of the globin genes. The shut-off in the expression of p53 always preceded the specific arrest of cells in the G0/G1 phase. Interferon did not modulate down the expression of p53 if added to transformed non-induced Friend-erythroleukemia cells; however, it slightly enhanced the extent of reduction in p53 synthesis if added during cell differentiation, thus suggesting a differential effect of interferon between cells at different stages of differentiation.
Animals↗
Increased exercise tolerance after nitroglycerin oral spray: a new and effective therapeutic modality in angina pectoris.
The prophylactic antianginal efficacy of nitroglycerin (NTG) oral spray was assessed in 20 patients with angiographically documented coronary disease and stable angina pectoris. The evaluation was by a randomized crossover trial involving treadmill exercise testing. On study day 1, a control treadmill exercise test was performed, followed 30 minutes later by a second exercise test 2 minutes after administration of either placebo (group A, 10 patients) or NTG spray 0.8 mg (group B, 10 patients). One week later, on study day 2, the patients again underwent control treadmill exercise testing followed by a second exercise test after either NTG spray (group A) or placebo (group B). NTG spray delayed the onset of anginal pain during exercise by a mean of 100 +/- 64 seconds (p less than 0.001) in 13 patients and prevented pain entirely in seven. Placebo did not significantly delay the appearance of angina and prevented chest pain in only one patient. NTG spray increased treadmill exercise duration by 31% before the onset of angina (p less than 0.001); placebo did not significantly alter the duration of exercise. NTG spray abolished in six patients and delayed in 14 patients the onset of exercise-induced ST-segment depression of 1 mm (p less than 0.001). Patients achieved a higher heart rate at peak exercise with NTG spray, and yet the maximal exercise-induced ST-segment depression of 2.1 +/- 1.0 mm during the control study declined to 1.3 +/- 0.9 mm on NTG spray (p less than 0.001). Placebo had no effect on exercise ST-segment depression. These data indicate that the oral NTG spray is an effective prophylactic for exercise-induced angina.
Administration, Oral↗
Immune complex glomerulonephritis and dermal vasculitis following intestinal bypass for morbid obesity.
A kidney and skin biopsy were performed on a patient who developed cryoglobulinemia, polyarthritis, a purpuric skin rash, and acute renal failure four years following jejunoileal bypass for morbid obesity. Morphologic studies revealed a diffuse glomerulonephritis characterized by the presence of numerous subendothelial deposits containing IgG, IgA, C3, Clq, C4, and properdin, and an acute dermal vasculitis associated with similar immune complex deposits. Identical immunoglobulin and complement components were present in the cryoglobulin. In addition, both the cryoglobulin and a renal biopsy eluate containing anti-IgG antibody and antibody against Klebsiella pneumoniae which were present in the patient's stool in large numbers. Combined therapy with steroids and chloramphenicol resulted in marked improvement in the patient's arthritis, skin rash, and renal function. The findings indicate that glomerulonephritis and dermal vasculitis due to the deposition of bacterial antigen-antibacterial antibody complexes may occur as part of a systemic immune complex disease complicating small intestinal bypass.
Adult↗
Initial characterization of a spontaneous interferon secreted during growth and differentiation of Friend erythroleukemia cells.
A gradual increase in the level of 2',5'-oligoadenylate synthetase takes place in Friend erythroleukemia cells after a shiftdown in the rate of cell growth. The increase is about 5-fold after entry of cells into the stationary phase of growth, but much higher (25-fold) when reduction in growth accompanies cell differentiation. In the latter case, the enzyme increase is similar to that which can be induced in these cells by exogenous interferon (IFN). The increase in 2',5'-oligoadenylate synthetase was shown to be due to a spontaneous secretion of IFN by the cells themselves: it is completely abolished if antiserum to murine type I IFN is added to the culture medium. In attempts to isolate some of this spontaneously secreted IFN, we show that it is stable at pH 2, not neutralized by antiserum to type II IFN, and that it also differs from the known IFN species induced by Sendai virus in Friend cells. The major component of this spontaneously secreted IFN is 20,000 M(r) and differs from the corresponding virus-induced 20,000-M(r) IFN by its lower affinity for antiserum to type I IFN and its antigenic characterization as beta-murine IFN. The major component of the spontaneous IFN also exhibits a higher ratio of antigrowth to antiviral activity than the Sendai-induced IFNs. We suggest that Friend cells produce this specific type of IFN for the regulation of their growth and differentiation.
2',5'-Oligoadenylate Synthetase↗
Antimitogenic effects of interferon and (2'-5')-oligoadenylate in synchronized 3T3 fibroblasts.
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Adenine Nucleotides↗
Efficacy of percutaneous transluminal coronary recanalization utilizing streptokinase thrombolysis in patients with acute myocardial infarction.
Since coronary thrombosis is a principal factor in the evolving necrotic process in the majority of patients with acute myocardial infarction (AMI), a prospective study was conducted in 25 AMI patients who underwent expeditious coronary arteriography. Of these patients, 22 with totally occluding thrombus also received early streptokinase (STK) administration. STK was given by intracoronary (20 patients) or systemic (two patients) infusion, 2000 to 50,000 IU/min, to a total dose of 125,000 to 500,000 IU within 10 hours of AMI symptom onset. Eighteen patients had angiographically visualized successful coronary thrombolysis; the shorter the interval between onset of symptoms to treatment, the more rapid was the clot dissolution. Successful thrombolysis occurred concomitantly with readily managed reperfusion ventricular tachyarrhythmias in nearly all patients. In addition, STK recanalization resulted in relief of ongoing chest pain in 10 of 12 patients, 10 of 16 evidenced immediate normalization of hyperacute ST segment abnormalities, and 8 of 14 demonstrated subsequent improvement of angiographically visualized left ventricular (LV) ejection fraction. In the percutaneous transluminal coronary recanalization (PTCR) procedure, the step of using a soft-tipped guide wire itself was transiently useful in only one of seven patients in whom this was attempted; reocclusion took place without added STK therapy. Nitroglycerin (NTG) alone produced only slight distal patency in but 1 of 19 patients with coronary occlusion given the nitrate. Importantly, in 14 control AMI patients receiving conventional treatment without STK, 10 showed angiographically complete occlusion of the coronary artery supplying the infarct region 1 month after infarction, thereby excluding spontaneous clot lysis mimicking STK-PTCR-induced reperfusion. These data support the concept that coronary occlusion by thrombosis is inherently involved with AMI and that rapid PTCR application of intracoronary STK provides potent thrombolysis, superior to that provided by NTG and guide wire passage in reestablishing coronary flow with attendant salvage of jeopardized myocardium and with subsequently improved LV function.
Adult↗