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Biomedical subjects

D Gemsa

Publications and source records attributed to D Gemsa.

At least 55 records · Page 3Linked to original sources
PubMed1996

Suppression of LPS-induced tumor necrosis factor-alpha gene expression by microtubule disrupting agents.

Microtubule disrupting agents such as colchicine have been shown to reduce TNF-alpha production in macrophages. To examine molecular mechanisms underlying the action of colchicine, TNF-alpha gene expression was studied in the murine macrophage cell line PU5-1.8. An LPS stimulation caused an intense up-regulation of TNF-alpha gene expression which was followed by a high TNF-alpha protein production. Simultaneous addition of colchicine (10 microM) suppressed LPS-induced TNF-alpha mRNA accumulation by one-third and TNF-alpha protein release by two-thirds. This effect was shared by vinblastine and vincristine, chemically different agents that also disrupt microtubule polymerization. For full suppressive activity on TNF-alpha gene expression, colchicine had to be present for 3 h in LPS-stimulated macrophage cultures. With nuclear run-on transcription experiments we could demonstrate that colchicine primarily inhibited de novo gene transcription and did not accelerate degradation of TNF-alpha mRNA in actinomycin D-treated macrophages. Thus, the well-known antiinflammatory action of microtubule depolymerizing agents may be largely due to a reduced TNF-alpha gene expression.

Animals↗
PubMed1996

Microbial transformation of 2,4,6-trinitrotoluene in aerobic soil columns.

2,4,6-Trinitrotoluene (TNT)-contaminated soil material of a former TNT production plant was percolated aerobically in soil columns. Nineteen days of percolation with a potassium phosphate buffer supplemented with glucose or glucose plus ammonium sulfate caused an over 90% decline in the amount of extractable nitroaromatics in soils containing 70 to 2,100 mg of TNT per kg (dry weight). In the percolation solution, a complete elimination of TNT was achieved. Mutagenicity and soil toxicity were significantly reduced by the percolation process. 4-N-Acetylamino-2-amino-6-nitrotoluene was generated in soil and percolation fluid as a labile TNT metabolite.

Journal Article↗
PubMed1996

The influence of the immunosuppressants OKT3 and ATG on immunological parameters.

Cytokines play an important role in the immune response induced by organ grafting, particularly during episodes of rejection. We tested the influence of monoclonal and polyclonal antibodies upon levels of mediators of the immune system. In 29 patients various cytokines and mediators were serially analyzed following transplantation. Thirteen patients received polyclonal antibodies (ATG) and 7 monoclonal (OKT3). Both OKT3 and ATG induced a rise in body temperature. Mean serum levels of amyloid A, neopterin, plasma levels of TNF alpha, interleukin 2 receptor (IL-2R) and urine levels of interleukin 6 (IL-6) and IL-2R were elevated when antibodies were employed. Interestingly, urine and plasma TNF-alpha as well as urine IL-6 and IL-2R remained elevated following ATG but not OKT3 and did not rise in case of basic treatment. In summary, antibody therapy increased levels of immune mediators. These mediators remained elevated following the discontinuation of treatment in case of ATG but not OKT3.

Acute Disease↗
PubMed1994

Characterization of a high molecular weight tumor necrosis factor-alpha mRNA in influenza A virus-infected macrophages.

Infection by influenza A virus has previously been shown to prime macrophages for a high TNF-alpha production. Influenza A virus induced a TNF-alpha mRNA accumulation that consisted of two types: a regular 1.7 kb and an additional high m.w. 2.4 kb species in murine macrophages, and a high m.w. 3.6 kb species in human monocytes. In this study, we further characterized this virus-induced, novel high m.w. TNF-alpha mRNA. The additional high m.w. TNF-alpha mRNA represented a true polyadenylated mRNA and its induction required exposure to infectious viruses. The regular and the high m.w. TNF-alpha mRNA were both found in the nuclear fraction and the cytoplasm. We excluded that the novel high m.w. TNF-alpha mRNA was an intron-containing precursor TNF-alpha mRNA that could have persisted in virus-infected macrophages. When TNF-alpha exons 1 to 4 and TNF-alpha exons 2 to 4 were amplified by polymerase chain reaction, only regular and no high m.w. bands were detected. By use of specific TNF-alpha intron I and intron III cDNA we could definitely demonstrate the absence of introns in the high m.w. TNF-alpha mRNA. The high m.w. TNF-alpha mRNA was free of TNF-beta and TNF intergenic region elements but contained the 5' and 3' untranslated region of TNF-alpha. Influenza A virus infection also induced a double band of IL-1 beta and IL-6 mRNA. Whether this novel high m.w. TNF-alpha mRNA represents a virus-induced abnormality or a superinduction of an otherwise normal but minor TNF-alpha transcript, and whether this high m.w. TNF-alpha mRNA species codes for a biologically active product, remains to be examined.

Animals↗
PubMed1994

Programmed cell death (apoptosis) in human monocytes infected by influenza A virus.

Although infection of monocytes by influenza A virus primes for a high cytokine release, it also leads to cell death within 20-30 hours. In this brief report, we demonstrate that influenza A virus-induced monocyte killing was due to programmed cell death (apoptosis) and not to necrosis. Morphologically, chromatin condensation and margination occurred and biochemically, an apoptosis-specific internucleosomal DNA fragmentation into multimers of 180 bp ("DNA ladder") was found. Induction of apoptosis and not necrosis in influenza A virus-infected monocytes may serve three purposes: 1. Virus replication is limited, 2. a priming for a high cytokine response is initiated and 3. damaging and inflammation-inducing lysosomal enzymes are held back from monocytes undergoing controlled cell death.

Apoptosis↗
PubMed1993

Effect of granulocyte/macrophage colony-stimulating factor on human monocytes infected with influenza A virus. Enhancement of virus replication, cytokine release, and cytotoxicity.

The activating properties of granulocyte/macrophage (GM)-CSF were studied in vitro with human monocytes infected by influenza A virus. When monocytes were pretreated for 8 h with GM-CSF (100 U/ml) and then exposed to influenza A virus, de novo virus protein synthesis was enhanced, more virus particles were released, and cells were killed at a higher rate. In virus-infected monocytes, GM-CSF induced a more rapid IFN-alpha release and potentiated production of TNF-alpha, IL-1 beta, and IL-6. Although GM-CSF or influenza A virus were each capable of independently activating TNF-alpha, IL-1 beta, and IL-6 gene transcription, a combination of both induced a massive cytokine mRNA accumulation which was readily translated into bioactive protein. Thus, GM-CSF may display a Janus-like action by accelerating virus infection but also by priming monocytes for elevated cytokine production. Whether the facilitated influenza A virus replication caused by GM-CSF may be counterbalanced by an improved cytokine response remains to be studied under more complex in vivo conditions.

Base Sequence↗
PubMed1993

Stress-induced changes of extracellular 5-hydroxyindoleacetic acid concentrations followed in the nucleus raphe dorsalis and the frontal cortex of the rat.

In the present paper, the effect of different stressors on extracellular 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the frontal cortex and the N. raphe dorsalis (NRD) of the rat were studied. The following stressful procedures were used: Immobilization, 10 min, cold, 20 min, and forced exercise in a rotating wheel, 2h. These procedures were compared with a handling procedure, 10 min. The extracellular 5-HIAA concentration was followed by in vivo voltammetry with carbon multifibre electrodes in the awake animal. Handling had no significant effect on extracellular 5-HIAA concentrations neither in the frontal cortex nor the NRD, whereas immobilization and cold evoked significant increases in both brain areas. During and after forced exercise a significant increase was measurable only in the frontal cortex, while extracellular 5-HIAA concentrations were unchanged in the NRD. Since it is very likely that the modulation of the activity of the central serotoninergic system under stressful conditions is closely connected with changes in behaviour and temperature regulation, we compared our findings on extracellular 5-HIAA levels during stress with the effect of the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), a substance known to reduce body temperature. The i.p. injection of a low dose decrease significantly both, the extracellular 5-HIAA concentration in the NRD and body temperature. Our results suggest that the serotoninergic activation in the frontal cortex may prove to be a general response to stress which could function perhaps as a part of the central coping mechanism, whereas serotonin (5-HT) in the NRD may modulate specific regulatory responses such as body temperature.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Tumor necrosis factor-alpha, interleukin 1, eicosanoid, and hydrogen peroxide release from macrophages exposed to glove starch particles.

The inflammatory mechanisms leading to glove starch powder peritonitis are still unclear. This study was designed to examine the secretory potential of macrophages exposed to starch powder particles. Rat peritoneal macrophages and human monocytes were incubated in vitro with starch particles obtained from three commonly used surgical gloves. It was found that macrophages and monocytes released large amounts of tumor necrosis factor-alpha, interleukin 1, prostaglandin E2, thromboxane B2, and hydrogen peroxide. Release of these inflammatory mediators was associated with progressive cell death of macrophages. These data indicate that postoperative peritonitis and subsequent granuloma formation initiated by glove powder particles may be mediated and maintained, at least in part, by macrophage-derived cytokines, eicosanoids, and reactive oxygen intermediates.

Animals↗
PubMed1993

The development of Pneumocystis carinii pneumonia in germ-free rats requires immunosuppression and exposure to the Pneumocystis carinii organism.

Adult germ-free rats treated with dexamethasone and exposed to a non-sterile environment did not harbor or develop Pneumocystis carinii cysts or trophozoites after 10 weeks of immunosuppression. Only when they were exposed to infected, conventional rats and treated with dexamethasone for 8 weeks or longer, did adult germ-free rats develop P. carinii infection.

Animals↗
PubMed1993

The potentiating effect of LPS on tumor necrosis factor-alpha production by influenza A virus-infected macrophages.

Infection of murine PU5-1.8 macrophages and human monocytes by influenza A virus was associated with virus replication, release of tumor necrosis factor-alpha (TNF-alpha) and subsequent cell death. In the presence of small and by itself rather inefficient concentrations of lipopolysaccharide (LPS) or free lipid A (1 to 10 ng/ml), TNF-alpha production of virus-infected macrophages was strongly potentiated. LPS-triggered and enhanced TNF-alpha release from virus-infected macrophages was neither due to increased cell survival nor altered virus replication, potentiated TNF-alpha gene transcription, release of intracellularly stored TNF-alpha or shifts in the kinetics of TNF-alpha secretion. Influenza A virus infection alone induced a massive TNF-alpha mRNA accumulation which, however, was only weakly translated into bioactive TNF-alpha protein. When these virus-primed macrophages were exposed to LPS either simultaneously or up to 4 h after infection, an efficient and high translation into TNF-alpha protein occurred. Although the LPS-induced biochemical pathways leading to an augmented TNF-alpha production by virus-infected macrophages still remains unsolved, the findings suggest that the frequently observed serious clinical complications in the course of combined influenza A virus and bacterial infections may be due, at least in part, to an excessive release of cytokines such as TNF-alpha.

Animals↗
PubMed1993

Role of macrophage cytokines in influenza A virus infections.

Human monocytes and murine macrophages were found to be susceptible to infection by influenza A virus. Although virus replication was low, infection led to cell death which was characterized by an extreme intracellular vacuolization. Most importantly, influenza A virus infection was accompanied by a particular pattern of cytokine release. Whereas IL-1 beta, IL-6 and TNF-alpha production was dependent on exposure to infectious virus, IFN-alpha/beta release was also induced by UV-inactivated virus. Although influenza A virus infection alone induced a substantial cytokine mRNA accumulation, translation into bioactive cytokine protein was rather limited. However, addition of low LPS concentrations was capable of strongly potentiating cytokine release from virus-infected cells. Thus, in a first step, an influenza A virus infection primes mononuclear phagocytes by leading to an accumulation of cytokine mRNA which, in a second step, may be readily translated into bioactive cytokines when triggering signals such as LPS are available. These findings suggest that influenza A virus represents an ultimately fatal macrophage activating factor which, when inducing moderate amounts of cytokines, may be beneficial by mounting an immediate antiviral response, but which may cause adverse effects when cytokine release is highly elevated by bacterial products.

Animals↗
PubMed1993

Immobilization and light-dark cycle-induced modulation of serotonin metabolism in rat brain and of lymphocyte subpopulations: in vivo voltammetric and FACS analyses.

The effect of immobilization and light-dark cycle on the serotoninergic system of the n. raphe dorsalis and on the distribution of blood lymphocyte subpopulations was studied in the rat. As was shown by in vivo voltammetry, 10 min immobilization enhanced serotonin metabolism with a maximum 15 min after immobilization. The distribution of the blood lymphocytes into subpopulations was also affected: pan-T and T helper lymphocytes were reduced during immobilization and reached minimum values after 20 min recovery. The circadian rhythms of serotonin metabolism and the distribution of pan-T and T helper cells exhibited a slight phase shift if compared with each other.

Animals↗
PubMed1992

Sensitization of rat alveolar macrophages to enhanced TNF-alpha release by in vivo treatment with dexamethasone.

Treatment of rats with dexamethasone rapidly induced a marked weight loss which occurred within 3 days and persisted for several weeks. The cachectic state was paralleled by increased serum levels of triglycerides, albumin, and protein and a strong reduction of blood mononuclear leukocytes. In lung sections, an increased number of mononuclear giant cells was found but no bacteria, fungi, or Pneumocystis carinii organisms. Quite strikingly, alveolar macrophages from dexamethasone-treated rats, but not from control animals, were highly sensitive to LPS and released large amounts of TNF-alpha ex vivo. Also under in vivo conditions, high TNF-alpha serum concentrations were found in dexamethasone-treated but not control rats when examined 1 1/2 hr after an intravenous LPS injection. These data suggest that the glucocorticoid-induced cachexia of rats may be linked, at least in part, to readily inducible TNF-alpha release from primed macrophages.

Animals↗
PubMed1992

The effect of adrenergic drugs on serotonin metabolism in the nucleus raphe dorsalis of the rat, studied by in vivo voltammetry.

The serotonin (5-HT) and norepinephrine (NE) system participate in the control of behavioural functions. The experiments were aimed at the question whether the NE system of the locus coeruleus interferes with the 5-HT activity of the nucleus raphe dorsalis and of which receptors are possibly involved. The alpha 1- and beta-adrenoceptor agonists methoxamine and isoproterenol, as well as a high dose (600 micrograms/kg i.p.) of the alpha 2-adrenoceptor agonist clonidine, increased extraneuronal 5-hydroxyindoleacetic acid (5-HIAA) levels in the nucleus raphe dorsalis as measured by in vivo voltammetry. In contrast, a low dose (60 micrograms/kg i.p.) of clonidine and the alpha 1-, alpha 2- and beta-adrenoceptor antagonists, prazosin, piperoxane, and atenolol, reduced the 5-HIAA concentration. In the locus coeruleus, the origin of NE projections to the nucleus raphe dorsalis, clonidine decreased whereas piperoxane enhanced extracellular 3,4-dihydroxyphenylacetic acid (DOPAC), an index of NE metabolism in the locus coeruleus. The results suggest that 5-HT neurotransmission in the nucleus raphe dorsalis is stimulated by the NE system of the locus coeruleus and that adrenoceptor drugs may affect 5-HT neuronal activity in addition to NE neurotransmission.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Coxsackievirus B3-induced production of tumor necrosis factor-alpha, IL-1 beta, and IL-6 in human monocytes.

Infections by coxsackievirus B3 (CVB3) have previously been shown to cause acute and chronic myocarditis characterized by a heavy mononuclear leukocyte infiltration and myocyte necrosis. Because clinical and experimental evidence suggested that cardiac damage may result from immunologic rather than viral mechanisms, we examined in this study the in vitro interaction of CVB3 with human monocytes. CVB3 was capable of infecting freshly harvested monocytes as revealed by immunofluorescence and release of infectious virus particles. Virus infection did not reduce monocyte viability but, on the contrary, enhanced spreading and adherence. In a dose-dependent manner, CVB3 stimulated the release of cytokines from monocytes. Whereas a potent production of TNF-alpha, IL-1 beta, and IL-6 was dependent on exposure to infectious CVB3, IFN release was also induced by UV-inactivated virus. On a molecular level, CVB3 stimulated cytokine gene expression as shown by a marked TNF-alpha, IL-1 beta, and IL-6 mRNA accumulation. Supernatants of CVB3-infected monocytes displayed cytotoxic activity against Girardi heart cells which could be abrogated by an anti-TNF-alpha antiserum. These data suggest that CVB3-induced cytokine release from monocytes may participate in virus-induced organ damage such as myocarditis, which may either occur by a direct cytotoxicity of cytokines or by activation of cytotoxic lymphocytes.

Cell Adhesion↗
PubMed1992

Serotonin-norepinephrine interactions: a voltammetric study on the effect of serotonin receptor stimulation followed in the N. raphe dorsalis and the Locus coeruleus of the rat.

In vivo voltammetry with carbon fibre electrodes was used to study the effect of the serotoninergic (5-HT) neuronal system on the noradrenergic (NE) system in the Locus coeruleus of the rat. The voltammetric DOPAC signal in the Locus coeruleus, used as a measure of NE neuronal activity, was increased after systemic application of the 5-HT1B agonist CGS-12066B, the 5-HT2 antagonist ritanserin, and, to a lesser extent, by ipsapirone, a 5-HT1A agonist. The findings suggest that the NE neuronal system of the Locus coeruleus is stimulated by 5-HT1A and 5-HT1B receptor activation and inhibited by 5-HT2 receptors. Likewise the 5-HT releaser and uptake inhibitor fenfluramine increased the DOPAC level in the Locus coeruleus. In contrast to the 5-HT1 agonists, which reduced 5-hydroxyindoleacetic acid (5-HIAA) in the Nucleus raphe dorsalis, ritanserin increased the 5-HIAA signal in this nucleus. This finding could help to explain the action of ritanserin as sleep-modulating substance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Enhanced release of cytokines, interleukin-2 receptors, and neopterin after long-distance running.

This study was designed to examine cytokine production in a group of 22 well-trained runners covering a distance of 20 km within 2 hr. After running, all participants displayed a marked granulocytosis for 7 hr. Plasma neopterin levels increased 1 hr after exercise for 24 hr. Except for interleukin-6 (IL-6), cytokines were not reliably detected in plasma but were present in urine. Already before exercise, cytokines were detected in the urine of runners when compared to sedentary controls. Directly after running, interferon-gamma and tumor necrosis factor-alpha were further elevated but rapidly declined to preexercise levels. Interleukin-1 beta and interleukin-6 increased at a slower rate after exercise but secretion into urine persisted longer until 12 and 7 hr, respectively. Interleukin-2 (IL-2) was not detected but soluble IL-2 receptors appeared in the urine directly after running. Enhanced cytokine levels were accompanied by an only low creatinin kinase increase, indicating little muscle damage. These data show that long-distance running elevates cytokine production which supports the concept that regular, but not excessive, physical exercise may be beneficial by maintaining a stimulated immune system.

Adult↗