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Biomedical subjects

F Herrmann

Publications and source records attributed to F Herrmann.

At least 127 records · Page 7Linked to original sources
PubMed1992

Interleukin 9 is expressed by primary and cultured Hodgkin and Reed-Sternberg cells.

We show by mRNA hybridization analysis and immunostaining using a mouse monoclonal antibody (moAb) to recombinant human interleukin 9 (IL-9) that both primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells produce IL-9 transcripts and protein and express surface binding sites for IL-9. In addition, the growth of H-RS cells obtained from the HDLM-2 line (abundantly producing IL-9 transcripts) was significantly inhibited when anti-IL-9 moAb or an IL-9 antisense oligodeoxyribonucleotide was added to cultures. Excess addition of recombinant human IL-9 relieved the effects of anti-IL-9 moAb on HDLM-2 growth. Growth of H-RS cells of the KM-H2 line, which displays only low amounts of IL-9 detectable upon hybridization of polyadenylic acid-selected RNA only, was not affected by anti-IL-9 moAb. The proliferative capacity of KM-H2 cells in soft agar and liquid suspension cultures was, however, augmented at least 3-fold when cells were exposed to recombinant human IL-9. In conclusion, our results show that IL-9 is expressed by H-RS cells and point to a possible role of this molecule as a growth factor for these cells.

Antibodies, Monoclonal↗
PubMed1992

Activation of the AP-1 transcription factor by arabinofuranosylcytosine in myeloid leukemia cells.

Previous studies have shown that 1-beta-D-arabinofuranosylcytosine (ara-C) induces transcription of the c-jun immediate early response gene in human myeloid leukemia cells. The present work has examined the mechanisms responsible for this effect. Deleted forms of the c-jun promoter were linked to the chloramphenicol acetyltransferase (CAT) gene and transfected into KG-1 cells. The results demonstrate that ara-C-induced c-jun transcription is mediated by an element between positions -74 and -20 upstream to the start site. Electrophoretic mobility shift assays with the fragment f(-74/-20) showed an increase in binding with nuclear proteins from ara-C-treated cells as compared with untreated cells. Competition with an oligonucleotide containing the AP-1 consensus sequence indicated that ara-C stimulates binding of nuclear proteins at the AP-1 site in the c-jun promoter. These findings were confirmed in other gel shift studies with the collagenase enhancer AP-1 consensus sequence and with a DNA fragment containing an altered AP-1 site. The binding of JUN/AP-1 was maximal at 1 hour of ara-C treatment and decreased to baseline levels at 12 hours. The finding that ara-C induces AP-1 binding in the absence of protein synthesis indicated that this agent activates already synthesized JUN/AP-1. To confirm these findings, the AP-1 consensus sequence was introduced 5' to the heterologous SV40 promoter. The results show that AP-1 enhances SV40 promoter activity in ara-C-treated cells. Taken together, these findings indicate that: (1) enhancement of JUN/AP-1 activity in ara-C-treated cells involves a posttranslational modification of JUN/AP-1; and (2) binding of activated JUN/AP-1 to the AP-1 site in the c-jun promoter confers ara-C inducibility of this gene.

Base Sequence↗
PubMed1992

Secretion of granulocyte-macrophage colony-stimulating factor by human blood monocytes is stimulated by engagement of Fc gamma receptors type I by solid-phase immunoglobulins requiring high-affinity Fc-Fc gamma receptor type I interactions.

Despite reports on the secretion of granulocyte-macrophage-colony-stimulating factor (GM-CSF) by murine peritoneal macrophages in response to inflammatory stimuli, the ability of human monocytes to generate this growth factor has remained doubtful. Neither endotoxin, phorbol compounds, nor inflammatory cytokines have been shown to elicit GM-CSF by these cells. Our present studies indicate that exposure of monocytes to solid-phase murine IgG2a, but not to murine IgG1 and thus cross-linkage of the 72-kDa Fc gamma RI results in transcription of the GM-CSF gene, accumulation of stable GM-CSF mRNA and finally in release of biologically active GM-CSF protein. Cross-linking of Fc gamma RI by a murine anti-Fc gamma RI monoclonal antibody and goat anti-mouse antibody failed, however, to stimulate GM-CSF release. This suggests that high affinity Fc-Fc gamma RI interactions are required for induction of expression of GM-CSF by monocytes.

Animals↗
PubMed1992

Leukotriene B4 transcriptionally activates interleukin-6 expression involving NK-chi B and NF-IL6.

Leukotriene B4 (LTB4) is a notable participant in inflammation and chemotaxis. It is, however, still unclear whether LTB4 acts in this regard directly or indirectly by stimulating the release of chemotactic and inflammatory cytokines. Here we report that LTB4 induces synthesis of interleukin (IL)-6 by human blood monocytes through transcriptional activation of the IL-6 gene. We furthermore demonstrate that this process involves activation of the transcription factor NF-chi B and, to a lesser extent, of NF-IL6, while the activity of the transcription factor AP-1, shown to otherwise confer IL-6 inducibility, appeared to be unaffected by LTB4. Involvement of NF-chi B and NF-IL6 in induction of IL-6 transcription by monocytes was demonstrated using deleted forms of the IL-6 promoter. Activation of the IL-6 promoter by LTB4 was not only associated with accumulation of the respective transcripts but resulted in synthesis of functional IL-6 protein as well. In addition, LTB4 mediated transactivation of a heterologous promoter construct containing the NF-chi B or the NF-IL6 enhancer, but not the AP-1 enhancer. The signaling events mediating this effect appeared to involve the release of H2O2, since LTB4 failed to induce NF-chi B or NF-IL6 in the presence of the scavenger of H2O2, N-acetyl-L-cysteine.

Binding Sites↗
PubMed1992

Identification of NF-jun, a novel inducible transcription factor that regulates c-jun gene transcription.

In this study we report the identification of a novel transcription factor, termed Nuclear Factor-jun (NF-jun). This factor contributes to inducible transcription of the c-jun gene in human myeloid leukemia cells. NF-jun was, however, undetectable in nuclear proteins from human monocytes, granulocytes, resting T lymphocytes and lung fibroblasts. NF-jun shares several features with the well characterized NF-kappa B in that binding activity can be generated in cytosolic extracts by treatment with dissociating agents. In addition, binding of NF-jun to its recognition site is enhanced by treatment of cells with 12-O-tetradecanoylphorbol-13-acetate, tumor necrosis factor alpha or the protein synthesis inhibitor cycloheximide (CHX). However, as revealed by competition assays and electrophoretic mobility shift assays, purified NF-kappa B fails to bind to the c-jun fragment which contains the NF-jun site, and this fragment fails to compete with NF-kappa B for binding. UV crosslinking showed that NF-jun contains a 55 and a 125 kDa protein species. These findings demonstrate that the c-jun gene can be regulated by a transcription factor distinct from AP-1. Our findings also indicate that while NF-jun has several features in common with the NF-kappa B binding protein including its subcellular localization and its ability to translocate from the cytoplasm to the nucleus, this factor recognizes a unique DNA sequence. Moreover, the activity of this protein is differentially regulated in various cell types. NF-jun might function as a signal transducing molecule in order to mediate rapid induction of the early response gene c-jun in a cell type- and stimulus-specific manner.

Base Sequence↗
PubMed1992

Expression of the proliferation-associated Ki-67 antigen of transferrin receptors and of DNA polymerase alpha in human tumour lines: implications for in vitro chemoresistance.

To compare the time course of in vitro expression of various proliferation-associated markers including Ki-67 antigen, transferrin receptors (TfR), and DNA polymerase alpha, six human tumour cell lines of different histological origin were studied under defined conditions. Proliferation markers were demonstrated by peroxidase/anti-peroxidase staining using specific monoclonal antibodies, and their expression was compared to results obtained from [3H]-thymidine incorporation assays and cell counting. Expression of all proliferation markers began to increase during the lag phase, and occurred earlier than elevations of [3H]dT incorporation and cell numbers were recorded. Maximum expression was observed before cell growth reached plateau phase. The time courses of expression of DNA polymerase and Ki-67 were almost identical. The closest correlation of [3H]dT incorporation with time course of expression of proliferation-associated markers was observed, when intranuclear staining of DNA polymerase was analysed. TfR were expressed earlier than the polymerase and Ki-67. Since TfR were also found at remarkable levels in resting cells, they seem less proliferation-specific than Ki-67 and DNA polymerase. While in rapidly growing cell lines more than 95% of the cells expressed Ki-67, TfR, and more than 75% DNA polymerase in cell nuclei, a malignant melanoma and a pleural mesothelioma line displayed fewer than 35% of cells stained for DNA polymerase in cell nuclei during log phase. Determination of growth fractions by monoclonal antibodies may thus contribute to the prediction of chemoresistance by identifying quiescent cells that are not sensitive to S-phase-specific drugs.

Cell Division↗
PubMed1992

Stimulation of growth of human malignant lymphoma and lymphoid leukemia cells in vitro.

We have analyzed cultures of malignant lymphoma cells and cells from patients with acute lymphoid leukemia in methylcellulose for their ability to from colonies. Clonogenic growth was examined in the presence or absence of fetal calf serum (FCS), platelet-poor plasma (PPP), medium conditioned by phytohemagglutinin-stimulated leukocytes (PHA-LCM), or irradiated allogeneic bone marrow stroma cells. Cells from 25 lymphoma patients--17 with non-Hodgkin's lymphoma (NHL), eight with Hodgkin's disease (HD)--and from 19 patients with acute lymphocytic leukemia (ALL) were investigated. We show that colony growth can be obtained in a minority of cases (in 3 NHL, 5 HD, and 2 ALL) and that the use of FCS and allogeneic irradiated stroma cells may be required for optimal colony formation.

Cell Division↗
PubMed1992

Interleukin 6: presence and future.

This review article deals with the basic biological characteristics of the multifunctional cytokine interleukin-6 (IL-6) in man. Three central issues will be addressed more closely: the pathophysiological role of unbalanced IL-6 production in various disease states, the diagnostic usefulness of measurements of IL-6 in biological fluids, and the possible role of IL-6, IL-6 antagonists, and IL-6 derivatives as therapeutic tools in clinical medicine.

Disease↗
PubMed1992

Detection of allele-specific expression of N-RAS oncogenes in human leukaemia cells.

We report analysis of allele-specific expression of N-RAS transcripts in myeloid leukaemic cells and cell lines. Expression was assessed by an assay of reverse-transcription/PCR combined with differential hybridization with mutation-specific oligonucleotides. In cells from all patients with acute myeloid leukaemia (AML) and in myeloid cell lines HL-60 and THP-1, expression of both the wild-type allele and the abnormal allele altered by a point mutation could be detected, albeit not always at comparable levels. This might be due for instance to allelic exclusion. The assay described provides a means of analysing the degree of expression of dominant oncogenes.

Acute Disease↗
PubMed1992

High levels of circulating soluble receptors for tumor necrosis factor in hairy cell leukemia and type B chronic lymphocytic leukemia.

The presence of soluble tumor necrosis factor (TNF) binding proteins (BP) was investigated in the sera of healthy volunteer blood donors and cancer patients. Two distinct types of TNFBP, types A and B, which are immunologically related to the cellular 75-kD TNF receptor (TNFR) and the cellular 55-kD TNFR, respectively, were assessed by immunoassays using nonblocking anti-receptor antibodies and 125I-recombinant human TNF alpha. As compared to the titers observed in 25 healthy controls, TNFBP types A and B titers were found to be elevated in almost all sera obtained from patients with underlying malignant disease. The highest amounts of TNFBP were seen in the sera of patients with B cell malignancies including hairy cell leukemia (HCL) and type B chronic lymphocytic leukemia. Treatment of HCL patients with recombinant human interferon-alpha was associated with decrease of circulating TNFBP.

Humans↗
PubMed1992

Elevated circulating levels of tumor necrosis factor predict unresponsiveness to treatment with interferon alfa-2b in chronic myelogenous leukemia.

PURPOSE: The study was undertaken to analyze circulating tumor necrosis factor (TNF) levels in patients with chronic-phase chronic myelogenous leukemia (CML) undergoing interferon (IFN) alfa-2b therapy, and to correlate pretreatment serum levels of TNF with response to IFN alfa-2b therapy. PATIENTS AND METHODS: Fourteen patients with CML in chronic phase were treated with recombinant human IFN alfa-2b for 7 to 39 months. RESULTS: In eight patients IFN alfa-2b treatment failed due to lack of hematologic response. A complete or partial hematologic remission was achieved in the remaining six patients, of whom two patients experienced a complete cytogenetic response. Retrospective analysis of serum samples obtained from all patients before the onset of IFN alfa-2b administration revealed that levels (mean +/- SEM) of circulating TNF were higher (P less than .001) in the group of patients who did not respond to IFN alfa-2b treatment (157 +/- 15 U/mL) than in the responders (10.3 +/- 4 U/mL) or healthy control subjects (9.1 +/- 3 U/mL). However, there was no correlation between TNF serum levels and other patient characteristics at study enrollment including age, sex, duration of disease, performance status, splenomegaly, WBC count, platelet count, hemoglobin value, prior therapy, and prognostic category. CONCLUSION: These findings indicate that circulating levels of TNF are increased in a subset of patients with chronic-phase CML and that this elevation is associated with poor response to IFN alfa-2b therapy.

Adult↗
PubMed1992

Combination of interleukin-2 and interferon-alpha in renal cell carcinoma and malignant melanoma: a phase II clinical trial.

A total of 22 patients with metastatic renal cell carcinoma or malignant melanoma were treated in a phase II study to assess the safety and efficacy of combination therapy of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). 3 x 10(6) U/m2/day recombinant human (rh)IL-2 was given in repetitive cycles by continuous 24-h infusion from day 1 to day 4; 6 x 10(6) U/m2/day rhIFN-alpha was given subcutaneously on days 1 and 4. There was one complete remission and two partial remissions in the renal cell carcinoma group and two partial remissions in the malignant melanoma group, giving an overall response rate of 24% in 21 evaluable patients with a median response duration of 5+ months. Toxicity was moderate, with hypotension, fever, chills, nausea, neurotoxicity, and dermatitis as prominent side effects. Measurement of circulating cytokine levels showed increased serum tumor necrosis factor-alpha (TNF), interferon-tau, and soluble interleukin-2 receptor levels during each cycle with a tendency to higher concentrations of TNF in responders as compared to nonresponders. With regard to therapeutic efficacy and tolerance, our approach might represent an alternative to the high-dose protocols and the labor- and cost-intensive strategies of adoptive immunotherapy.

Adult↗
PubMed1992

[The behavior of trypsin-like proteases in sulcus fluid].

The present study shows results aimed at determining whether levels of a trypsin-like protease in gingival crevicular fluid are associated with disease activity as assessed by the level of gingival inflammation and probing attachment loss. Maximum enzyme level was significantly elevated by groups with gingival inflammation and periodontal destruction. In a long-time study we find a decrease of enzyme activity with clinical therapy by scaling and root planning.

Adolescent↗
PubMed1992

[Hemolytic disease of the newborn due to ABO incompatibility. A predictive test].

A direct 2 stage enzymatic test and the direct anti gamma globulin test were used to predict hemolytic disease of the newborn. Maternal allo-antibodies were determined in cord blood of all newborns from April to June 1988. 0.25% bromelase was used for the 2 Stage Enzymatic Test and a polyspecific anti-gammaglobulin serum was used for the Anti Gamma Globulin Test. Of 618 newborns 97 had parental ABO heterospecificity. Maternal allo-antibodies were present in 20 cases (3.2%). 20 of 86 fullterm newborns developed jaundice presumably due to ABO incompatibility. Blood exchange was required in 6, while phototherapy was sufficient in the rest. The 2 Stage Enzymatic Test was positive in 20 of these cases and the Anti Gamma Globulin Test was positive in 10. Thus, these tests may be used to predict hemolytic disease of the newborn due to ABO incompatibility.

ABO Blood-Group System↗
PubMed1992

Hematopoietins in combination with 1-beta-D-arabinofuranosylcytosine: a possible strategy for improved treatment of myeloid disorders.

Inhibitors of DNA synthesis, such as 1-beta-D-arabinofuranosylcytosine, have been proven useful in the management of acute myelogenous leukemia. Despite significant improvement of response rates, long-term disease-free survival can be presently achieved only in a small percentage of patients. As S-phase--specific drugs, such as the inhibitors of DNA synthesis, only reach the cycling part of their target populations, dormant cells are left mainly unaffected. Their survival, however, is largely responsible for later disease relapse. This paper reports experiments that show that cell kinetic manipulations by hematopoietic growth factors may help to overcome the problem of cytokinetic and pharmacologic resistance. Hematopoietic growth factors synergize with inhibitors of DNA synthesis given at low doses to induce a more mature phenotype or to enhance leukemia cell kill when combined with high doses of DNA inhibitors. In addition, we present data to unravel several aspects of the molecular mechanism underlying this synergism.

Acute Disease↗
PubMed1992

Effect of antiinflammatory agents on synthesis of MCP-1/JE transcripts by human blood monocytes.

The human monocyte chemoattractant protein (MCP)-1 encoded by the JE gene belongs to a family of low molecular weight secretory cytokines with monocyte-stimulating activity. JE transcripts are constitutively synthesized by normal and leukemic monocytes, as well as mesenchymal cells, including fibroblasts, vascular endothelial cells, and smooth muscle cells. Expression of MCP-1/JE is increased severalfold upon exposure of cells to recombinant human granulocyte-macrophage colony-stimulating factor but is down-regulated when cells are treated with lipopolysaccharide (LPS). Given the proinflammatory properties of MCP-1/JE, we have examined the modulatory effects of various antiinflammatory agents, including indomethacin, dexamethasone, cyclosporin A, and interleukin-4, on levels of MCP-1/JE transcripts either constitutively or inducibly expressed by human peripheral blood monocytes. Whereas indomethacin had no detectable effect on synthesis of MCP-1/JE transcripts and interleukin-4 treatment resulted in only a modest increase in steady state JE mRNA levels, exposure of monocytes to dexamethasone (DXS) led to a significant (2.5-10-fold) down-regulation of MCP-1/JE transcript levels. Studies examining the mechanism of down-regulation of JE mRNA by DXS indicated that DXS was acting transcriptionally and posttranscriptionally, by reducing the transcriptional rate of the MCP-1/JE gene and by destabilizing JE mRNA, a process requiring de novo RNA and protein synthesis. Although cyclosporin A by itself had no effect on synthesis of JE transcripts, it apparently relieved LPS-mediated down-regulation of JE transcript levels, by interfering with the destabilizing effect of LPS on JE mRNA. These results may provide new information regarding the action of antiinflammatory agents on synthesis of endogenous proinflammatory cytokines.

Anti-Inflammatory Agents↗