Biomedical subjects
Publications and source records attributed to U Gullberg.
Composition of azurophil and specific granules from human polymorphonuclear neutrophils and granules from eosinophils is presented. Biosynthesis of the granule proteins is discussed in detail with particular emphasis on neutrophil myeloperoxidase (MPO) and eosinophil cationic protein (ECP).
A differentiation-inducing factor (DIF) for the promyelocytic HL-60 cell line is constitutively produced by the malignant T lymphocyte line HUT-102. DIF was highly purified from HUT-102-conditioned media by means of diethylaminoethanol (DEAE)-chromatography, gel chromatography, and high-resolution, ion-exchange chromatography on a MonoQ column and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In addition to inducing differentiation of wild-type HL-60 cells, resulting in secondary inhibition of growth, DIF, at a tenfold lower concentration, inhibited the growth of some clones of the monoblastic U-937 cell line as well as that of subclones of HL-60. The latter effect was most likely a primary growth inhibition and not secondary to differentiation; 50% inhibition of clonogenic growth in agar was seen at approximately 1.0 pmol/L of DIF. In addition, the clonogenic growth of fresh leukemia cells from 10 of 12 patients with acute myeloid leukemia (AML) was inhibited with 50% inhibition at approximately 10 pmol/L of DIF. The growth of normal granulocyte-macrophage colonies was inhibited at a similar concentration, whereas early erythroid colonies were much more resistant. DIF and interferon-gamma (gamma-IFN) were shown to be separate molecules inasmuch as a neutralizing antibody for gamma-IFN did not abolish the DIF effect. The differentiation effect on wild-type HL-60 and the proliferation inhibitory effect on leukemic and normal myeloid cells cochromatographed through all purification steps suggest that both activities are exhibited by identical polypeptides. DIF may have a role in regulating normal hemopoiesis. The growth inhibitory effect of DIF and the ability to induce differentiation of some leukemia cells may suggest a clinical utility in the treatment of leukemia.
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The monoblastlike leukemia cell line, U-937, is induced to differentiate into monocytelike cells by incubation with 200-500 U/ml of recombinant human immune interferon (IFN-gamma) judging from capacity to reduce nitroblue tetrazolium. At least an additive differentiation-inducing effect was found between IFN-gamma and 1-100 nM retinoic acid (RA). A marked synergistic differentiation-inducing effect was found between IFN-gamma and 0.1-1.0 nM 1 alpha,25-dihydroxycholecalciferol (1,25[OH]2D3). It is also shown that U-937 can be primed for differentiation by treatment for approximately one day with 1,25(OH)2D3 followed by exposure to IFN-gamma. Priming of these cells does not depend on the normal rate of RNA synthesis, as it occurs even better in the presence of cordycepin, suggesting that a decrease in RNA synthesis favors IFN-induced differentiation. Actually, the addition of cordycepin during initial incubation with IFN increased the subsequent response to IFN-gamma (and also to RA and 1,25[OH]2D3). These results, indicating that combinations of IFN-gamma and either RA or 1,25(OH)2D3 induce differentiation of U-937, may be of importance in combination biotherapy of leukemia.
Some clones of the human histiocytic lymphoma line, U-937, were induced to differentiate into monocyte-like cells with loss of plating efficiency in agar by incubation with 0.1 to 10 nM 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3]. At 1 nM, 40% of the cells of one sensitive clone exhibited differentiation after 2 days of incubation judging from assays for phagocytosis and capacity to reduce nitroblue tetrazolium. Induction appeared to occur by binding of the cholecalciferol to a specific cytoplasmic and/or nuclear receptor for 1,25(OH)2D3. However, the presence of this receptor was not sufficient for differentiation, since one clone which contained the receptor did not respond with differentiation upon addition of 1,25(OH)2D3. Differentiation induction did not require DNA synthesis but was blocked by agents which inhibit RNA or protein synthesis. It was also blocked by the calcium ionophore A 23187. A synergistic inducing effect was seen between 1,25(OH)2D3 and retinoic acid. In addition, the U-937 cells could be primed by a short incubation with 1,25(OH)2D3 to respond, with maturation, to the addition of agents which increase the intracellular level of cyclic adenosine 3':5'-monophosphate, such as prostaglandin E2, cholera toxin, and N6,O2'-dibutyryl adenosine 3':5'-monophosphate and which alone did not induce differentiation. Priming does not depend on the normal rate of RNA or protein synthesis, since it was not significantly inhibited by actinomycin D, cordycepin, or cycloheximide. It remains to be determined if unoccupied receptors for 1,25(OH)2D3 are present in fresh leukemia cells and if such cells can sometimes be induced to differentiate upon addition of cholecalciferol.
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Inhibitors of Tumour Necrosis Factor (TNF) may be necessary for protection of the host against harmful systemic manifestations of this cytokine such as in the septic syndrome and inflammatory conditions. TNF-binding proteins (TNF-BP) have been identified and shown to be the soluble extracellular domains of two transmembrane TNF receptors produced by proteolytic cleavage. TNF-BP inactivates TNF by formation of high affinity complexes thereby reducing the binding of TNF to target cell membrane receptors. In addition, TNF is stabilized in complex with TNF-BP, and under certain conditions the complex may act as a slow releaser of biologically active TNF. TNF can induce the release of TNF-BP in vivo which might neutralize the bioactivity of TNF. Cytokine control by natural and recombinant cytokine inhibitors such as TNF-BP could be a promising therapeutic approach in chronic inflammatory disorders to shift the balance between a cytokine-induced response and counteracting "anticytokines". A local production of TNF-BP in some tumour tissues may inactivate TNF for the benefit of the tumour. In some leukemias e.g. B-cell chronic lymphocytic leukemia, where TNF can act as a growth factor for the malignant cells, TNF-BP may be growth inhibitory.