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Results for “Receptors, Interleukin-3”

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At least 19 recordsLinked to original sources

PubMed1992

The erythropoietin receptor transmembrane region is necessary for activation by the Friend spleen focus-forming virus gp55 glycoprotein.

The erythropoietin receptor (EPO-R), a member of the cytokine receptor superfamily, can be activated by binding either erythropoietin (EPO) or gp55, the Friend spleen focus-forming virus glycoprotein. The highly specific interaction between gp55 and EPO-R triggers cell proliferation and thereby causes the first stage of Friend virus-induced erythroleukemia. We have generated functional chimeric receptors containing regions of the EPO-R and the interleukin-3 receptor (AIC2A polypeptide), a related cytokine receptor which does not interact with gp55. All chimeric receptors were expressed at similar levels, had similar binding affinities for EPO, and conferred EPO-dependent cell growth. Only those chimeric receptors which contained the EPO-R transmembrane region were activated by gp55. These results demonstrate that the transmembrane region of the EPO-R is critical for activation by gp55. In addition, analysis of a soluble, secreted EPO-R and cysteine point mutants of the EPO-R show that the extracytoplasmic region of the EPO-R specifically interacts with gp55.

Binding Sites↗

PubMed1992

Modulation of GM-CSF receptor beta-subunit and interleukin-6 receptor mRNA expression in a human megakaryocytic leukemia cell line.

Our present study was designed to clarify the mechanism by which the same megakaryocyte progenitor cells respond to various cytokines at different stages of megakaryocyte development. We examined the changes in mRNA expression of granulocyte macrophage colony-stimulating factor receptor beta-subunit (GM-CSFR beta-subunit), which was a common subunit of a high-affinity interleukin-3 receptor (IL-3R) and a high-affinity GM-CSFR, and interleukin-6 receptor (IL-6R) during megakaryocyte development in a human megakaryocytic leukemia cell line (CMK) which could proliferate and/or differentiate in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), IL-3, GM-CSF, and IL-6. We found that GM-CSFR beta-subunit mRNA was expressed constitutively in CMK cells and was transiently down-regulated by TPA and IL-6, while the expression of IL-6R mRNA was increased by TPA in association with the differentiation of megakaryocytes. Furthermore, the TPA-induced down-regulation of GM-CSFR beta-subunit mRNA expression and its recovery were blocked by cycloheximide (CHX), a protein synthesis inhibitor, suggesting that these modulations required de novo protein synthesis. These findings imply that multi-lineage cytokines such as GM-CSF and IL-3 may contribute preferentially to the regulation of the earlier development of megakaryocyte progenitor cells with high densities of multi-lineage cytokine receptors, while IL-6 may be limited in its action to supporting the maturation of more differentiated megakaryocyte progenitor cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗

PubMed1992

Rapid priming of human monocytes by human hematopoietic growth factors: granulocyte-macrophage colony-stimulating factor (CSF), macrophage-CSF, and interleukin-3 selectively enhance superoxide release triggered by receptor-mediated agonists.

The effects of hematopoietic growth factors on human monocyte superoxide (O2-) release were investigated by using purified human monocytes in suspension. Among growth factors studied, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (M-CSF), and interleukin-3 (IL-3) primed human monocytes and enhanced O2- release stimulated by the receptor-mediated agonists, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate, which bypasses the receptors to stimulate the cells. The optimal priming was obtained by pretreatment of cells with 1 to 5 ng/mL (0.07 to 0.34 nmol/L) GM-CSF, 50 to 100 ng/mL (0.5 to 1.1 nmol/L) M-CSF, or 10 to 20 ng/mL (0.6 to 1.3 nmol/L) IL-3 for 10 minutes at 37 degrees C. Potency of the maximal priming effects on FMLP- or Con A-induced O2- release was GM-CSF greater than M-CSF = IL-3. The combination of the optimal concentrations of any two CSFs resulted in the effect of more potent priming agent alone. Enhancement of O2- release by GM-CSF was observed over the complete range of effective concentrations of FMLP (10(-8) to 10(-6) mol/L). The pretreatment of monocytes with granulocyte-CSF (50 ng/mL), interferon-gamma (1,000 U/mL), or IL-4 (20 ng/mL) for 10 minutes at 37 degrees C had no effect on O2- release stimulated by FMLP or Con A. These findings show that GM-CSF, M-CSF, and IL-3 selectively enhance O2- release in human monocytes triggered by receptor-mediated agonists after short-term preincubation.

Adult↗

PubMed1992

IFN-gamma induces expression of Fc gamma RIII (CD16) on human eosinophils.

The extent to which eosinophils constitutively express FcRIII (CD16) is controversial. We were unable to detect this receptor on freshly isolated, peripheral blood eosinophils. The capacity of eosinophils to change their Fc gamma R expression in vitro has not been previously demonstrated. Culture with IFN-gamma for 1 to 2 days induced FcRIII expression on eosinophils. This effect was dose-dependent and significant at concentrations of 100 U/ml IFN-gamma and above. Expression of FcRI (CD64) and FcRII (CDw32) was also upregulated. These increases were inhibited by cycloheximide (10(-6) M), suggesting a requirement for protein synthesis, and dexamethasone (10(-6) M). Northern blot analysis demonstrated the presence of FcRIII mRNA in eosinophils cultured with IFN-gamma for 2 days but not in unstimulated eosinophils. By contrast, culture with IL-3 caused an up-regulation of eosinophil FcRII expression but did not induce expression of FcRI or FcRIII. The FcRIII expressed by eosinophils after IFN-gamma stimulation was functionally active, as shown by the triggering of eosinophil membrane depolarization and LTC4 generation by an anti-CD16 mAb. Treatment of IFN-gamma-stimulated eosinophils with phosphatidylinositol-specific phospholipase C reduced FcRIII expression, suggesting that, like neutrophils, eosinophils express the phosphatidylinositol glycan-linked form of this receptor. Therefore, this study demonstrates that IFN-gamma-treated eosinophils express a functionally active, phosphatidylinositol glycan-anchored form of FcRIII.

Antigens, Differentiation↗

PubMed1992

Role of protein kinase C and the Na+/H+ antiporter in suppression of apoptosis by granulocyte macrophage colony-stimulating factor and interleukin-3.

Granulocyte macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) suppress apoptosis in hemopoietic cells, a process of active cell death characterized by the degradation of genomic DNA into oligonucleosomic fragments. The present study was therefore initiated with the view that the two growth factors may trigger the same early events in the cell, leading to suppression of apoptosis. We provide evidence here for a role of protein kinase C and of the Na+/H+ antiporter in the signal transduction pathways activated by binding of GM-CSF or IL-3 to their respective receptors, resulting in suppression of apoptosis in target cells. First, kinetic studies indicate that the process is irreversible after two hours of deprivation. The suppression of apoptosis by GM-CSF and IL-3 is dose-dependent, with half-efficient concentrations that are in the range of the dissociation constants of the high affinity GM-CSF or IL-3 receptor, respectively. Second, the use of three inhibitors of protein kinase C (PKC), H7, staurosporine, and sphingosine, in concentrations that are below their toxicity limits, revert the suppression of apoptosis by IL-3 and GM-CSF. Conversely, the use of 12-O-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, allows a bypass of receptor activation in suppression of apoptosis. Western blotting of cytosolic and membrane proteins indicate that exposure of the cells to GM-CSF, IL-3, or TPA results in translocation of PKC to the cell membrane. Our data, therefore, indicate that the activation of PKC is important in suppression of apoptosis by GM-CSF and IL-3. Third, the two amiloride derivatives 5-(N,N-hexamethylene) and 5-(N-ethyl-N-isopropyl)amiloride that specifically block the function of the Na+/H+ antiport also revert the protective effect of GM-CSF, IL-3, and TPA on MO7-E cells. Further, exposure of the cells to GM-CSF, IL-3, or TPA results in sustained pHi alkalinizatio, which is abrogated when the cells are preincubated with 5-(N-ethyl-N-isopropyl)amiloride, a specific inhibitor of the antiport. Preincubation of the cells with staurosporine, a PKC inhibitor, also significantly reduces the effect of GM-CSF or IL-3 on pHi. Taken together, our data indicate that a functional antiport is required in suppression of apoptosis by GM-CSF, IL-3, or TPA. Furthermore, our results are consistent with the view that GM-CSF or IL-3 receptor activation initiates the sequential activation of PKC and of the Na+/H+ antiporter, resulting in suppression of apoptosis in target cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Induction of erythropoietin responsiveness in murine hematopoietic cells by the gag-myb-ets-containing ME26 virus.

ME26 virus, which was generated by inserting the coding region of the acute avian leukemia-inducing virus E26 into a murine retrovirus vector, encodes a 135-kDa gag-myb-ets fusion protein. Amphotropic murine leukemia virus pseudotypes of ME26 virus induce a high incidence of erythroleukemia 2 to 4 months after injection into newborn NFS/N mice. Spleen cells from the majority of these mice proliferate to high levels in the presence of the erythroid hormone erythropoietin (Epo) and can easily be established as permanent Epo-dependent cell lines. The cell lines contain multiple copies of ME26 viral DNA and express viral message and protein. An Epo receptor mRNA of normal size can be detected in these cells, and binding studies reveal a single class of lower-affinity Epo receptor with an affinity for Epo that is in the range of that previously reported for erythroid cells. The ME26 virus-induced Epo-dependent cell lines, however, appear more immature than previously described erythroid cell lines and more closely resemble early hematopoietic precursor cells, suggesting that the virus may be activating the Epo receptor in hematopoietic cells that do not normally express it. Consistent with this idea, we are able to infect an interleukin-3-dependent myeloid cell line, FDC-P2, with ME26 virus and convert it to Epo dependence. The ME26 virus-infected FDC-P2 cells, even before growth on Epo, showed a large increase in the amount of Epo receptor mRNA. However, no ME26 viral integrations can be detected adjacent to the Epo receptor gene, indicating that the virus is not activating the Epo receptor gene by promoter/enhancer insertion. Our results are more consistent with the hypothesis that the gag-myb-ets-encoded viral fusion protein, which is known to bind DNA, is directly or indirectly activating the expression of the Epo receptor gene in these cells.

Animals↗

PubMed1992

Immunomodulatory effect of peripheral benzodiazepine receptor ligands on human mononuclear cells.

Immunomodulatory effect of ligands active at the peripheral benzodiazepine receptor (PBR) was examined in human peripheral blood mononuclear cells (PBMC). Ro5-4864, PK11195 and diazepam suppressed phytohemagglutinin (PHA) and concanavalin A (ConA) induced proliferation of PBMC. All three ligands inhibited interleukin-3-like activity (IL-3-LA) secretion, while the production of interleukin-2 (IL-2) was inhibited by Ro5-4864 and diazepam only. The selective central benzodiazepine ligand clonazepam did not affect the cellular immune functions examined. Our results indicate an in-vitro immuno-suppressive activity of peripheral and mixed, but not central type benzodiazepine ligands.

Adjuvants, Immunologic↗

PubMed1992

In vitro phosphorylation of the erythropoietin receptor and an associated protein, pp130.

The cytoplasmic domain of the cloned erythropoietin (EPO) receptor (EPOR) contains no protein kinase motif, yet addition of EPO to EPO-responsive cells causes an increase in protein-tyrosine phosphorylation. Here we show that addition of EPO or interleukin-3 (IL-3) to an IL-3-dependent cell line expressing the wild-type EPOR causes a small fraction (less than 5%) of total cellular EPOR to shift in gel mobility from 66 to 72 kDa, due at least in part to phosphorylation. Using biotinylated EPO as an affinity reagent, we show that the 72-kDa species is greatly enriched on the cell surface. To demonstrate that a protein kinase activity associates with cell surface EPOR, cells were incubated with biotinylated EPO and then cross-linked with a thiol-cleavable chemical cross-linker. The avidin-agarose-selected complexes were incubated with [gamma-32P]ATP. After in vitro phosphorylation and denaturation without reducing agent, both antiphosphotyrosine and anti-EPOR antibodies immunoprecipitated labeled 72-kDa EPOR and an unidentified 130-kDa phosphoprotein (pp130), indicating that a protein kinase is associated with cell surface EPOR and that a fraction of the EPOR was phosphorylated on tyrosine residues either in the cells or during the cell-free phosphorylation reaction. Under reducing conditions, the 72-kDa phosphorylated EPOR but not pp130 was immunoprecipitated with an anti-EPOR antibody, suggesting that the pp130 is bound to the EPOR by the thiol-cleavable chemical cross-linker. Previously, we showed that deletion of the 42 carboxy-terminal amino acids of the EPOR allows cells to grow in 1/10 the normal EPO concentration, without affecting receptor number or affinity. Two carboxy-terminal truncated EPO receptors that are hyperresponsive to EPO were poorly phosphorylated during the in vitro reaction, suggesting that the carboxy-terminal region of the EPOR contains a site for phosphorylation or a site for interaction with a protein kinase. Our data suggests that phosphorylation or interaction with a protein kinase in the carboxy-terminal region may down-modulate the proliferative action of the EPOR.

Amino Acid Sequence↗

PubMed1992

Tryptophan residue of Trp-Ser-X-Trp-Ser motif in extracellular domains of erythropoietin receptor is essential for signal transduction.

The Trp-Ser-X-Trp-Ser motif commonly exists just outside the transmembrane domains of all cytokine receptors so far isolated. The role of this conserved motif in erythropoietin receptor was examined by assessing a series of mutant receptors on erythropoietin-induced signal transduction. Replacement of one of the two conserved Trp residues in the motif to Gly was found to completely abolish the binding of erythropoietin to the receptor and also to lose the ability to transduce the factor-dependent growth signal. While the mutants with one Ser residue converted to Gly or Ala retained full biological activities, the replacement of both conserved Ser residues diminished the functions of the receptor. Furthermore, the receptors lacking a part or all of the Trp-Ser-X-Trp-Ser motif did not respond to erythropoietin. The Trp-Ser-X-Trp-Ser motif, especially Trp residue, located in extracellular domains of the erythropoietin receptor thus appears to play a critical role in receptor-mediated signal transduction.

Amino Acid Sequence↗

PubMed1992

Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor.

The erythropoietin receptor (EPOR) is a member of the newly identified cytokine receptor superfamily. A common sequence motif, Trp-Ser-X-Trp-Ser (WSXWS), near the transmembrane domain is highly conserved in this family. To determine the function of this motif, we constructed deletion and insertion mutations in this part of the EPOR and introduced them into an interleukin-3 (IL-3)-dependent hematopoietic Ba/F3 cell line. Cells expressing the wild-type EPOR displayed 1,500 erythropoietin (EPO)-binding sites/cell with a single affinity of about 300 pM and proliferate in the presence of IL-3 or EPO. Ba/F3 cells expressing receptors mutated in the WSXWS motif displayed little EPO binding on the cell surface and did not grow in the presence of EPO. The mutant receptors were retained in the endoplasmic reticulum (ER) and, as such, were unable to bind EPO. A single Gly insertion between the two WS sequences caused defects in receptor structure and function similar to mutations lacking all or part of the WSXWS motif. The EPOR can be activated, resulting in proliferation independent of EPO either by an Arg129 to Cys point mutation or by association with the Friend spleen focus-forming virus (SFFV) envelope glycoprotein gp55. Introduction of the point mutation (Arg129 to Cys) did not activate any of the receptors mutated in the WSXWS motif. Moreover, gp55 did not activate the mutant receptors in Ba/F3 cells. Our study indicates that the WSXWS motif is critical for protein folding, ligand-binding, and signal transduction.

Amino Acid Sequence↗

PubMed1992

Modulation of macrophage response to interleukin-2 immunotherapy by interleukin-3 in cancer patients.

It has been observed that neopterin, a specific marker of macrophage activation, increases during cancer immunotherapy with IL-2, and this effect is mediated by interferons produced by IL-2-stimulated lymphocytes. Moreover, our previous studies have shown that neopterin rise during IL-2 immunotherapy is associated with an enhanced release of soluble IL-2 receptor (SIL-2R), which may suppress IL-2-dependent immune functions. This finding would suggest that neopterin increase may be related to the generation of suppressive events, which occur during IL-2 immunotherapy. On the basis of the documented modulatory effect of IL-3 on macrophage functions, we have evaluated the influence of IL-3 on neopterin secretion during IL-2 immunotherapy. The study was performed in advanced lung cancer patients. We have investigated 9 immunotherapeutic courses consisting of IL-2 (6M IU/day s.c. for 5 days/week for 3 weeks) plus IL-3 (1 microgram/(kg x day) i.v. for 14 days, starting 7 days before IL-2). The results were compared to those found during 18 courses with IL-2 alone. Mean neopterin levels increased significantly during IL-2 alone, but not in response to IL-3 plus IL-2. SIL-2R rise was significantly higher during IL-2 than during IL-3 plus IL-2. Mean numbers of NK cells and activated lymphocytes increased significantly in both groups of patients, but were significantly lower at the end of the treatment in patients receiving IL-2 alone than in those treated with IL-3 plus IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1992

Biological characteristics of CD7 positive acute myelogenous leukaemia.

We studied the biological characteristics of CD7+ acute myelogenous leukaemia (AML). We diagnosed nine out of 88 consecutive AML cases as CD7+ AML based on myeloperoxidase positivity and surface antigen expression. In eight of these nine cases more than 20% of leukaemic blasts were found to coexpress both CD7 and a myeloid-associated antigen, CD33, by a two-colour flow-cytometric assay, while in the remaining case more than 90% of blasts were positive for CD7 and myeloperoxidase. CD7+ AML was most frequently observed in M1 among AML subtypes according to the FAB classification. An early stage-specific antigen, CD34 was also expressed on leukaemic blasts from eight of these nine cases. Neither the T-cell receptor (TcR)-beta nor the TcR-gamma gene was clonally rearranged in any of the cases. We then studied the proliferative responses to stimulation by various growth factors. Among interleukin-3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), and granulocyte-CSF (G-CSF), IL-3 showed the strongest stimulatory effect on DNA synthesis and leukaemic blast colony formation in 8/9 and 6/8 CD7+ AML cases examined, respectively. On the other hand, the strongest stimulatory effect exerted by IL-3 on blast colony formation was observed in only six out of the 33 CD7- AML cases examined. Furthermore, CD7+ AML blasts could proliferate in response to stem cell factor (SCF); SCF alone showed stimulatory effects on blast colony formation (7/8 cases), and in 5/7 SCF-responding cases, stimulatory effects of SCF were more potent than those of IL-3. In addition, SCF enhanced blast colony formation synergistically with IL-3 in four of these seven cases. These data suggest that progenitor cells of CD7+ AML may possess the biological properties characteristic of immature haematopoietic stem cells.

Adolescent↗

PubMed1992

Sustained expression of the pim-1 kinase is specifically induced in myeloid cells by cytokines whose receptors are structurally related.

We have examined the effects of myeloid growth factors on expression of the pim-1 kinase protein in human and murine myeloid cells. pim-1 protein was identified in K562 cells by immunoblotting as a 33 kDa protein. In the human factor-dependent myeloid leukemia cell line M07E, pim-1 protein was induced by interleukin 3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), with maximum expression by 4 h. Expression continued for the duration of growth factor exposure, but declined rapidly when cytokines were removed. GM-CSF induced pim-1 protein in a dose-dependent manner, with expression being proportional to the proliferative effect of the cytokine. To examine the specificity of pim-1 protein induction, we compared pim-1 protein levels in myeloid cells which demonstrated different GM-CSF response phenotypes. We also examined the effects on pim-1 protein expression of different growth factors which induced similar response phenotypes. GM-CSF induced pim-1 protein in several myeloid cell lines, most of which demonstrated a proliferative response, but did not induce pim-1 protein expression in neutrophils or monocytic cells. In contrast, the murine cell line Mac-11 expressed pim-1 message in response to IL-3 and GM-CSF, but not in response to bryostatin or M-CSF, which were equivalent mitogens. In human U937 myeloid cells sustained expression of pim-1 protein was induced by GM-CSF, G-CSF and IL-6, but not by bryostatin. Expression of the pim-1 kinase protein in response to myeloid cytokines depends on both the nature of the growth factor and the response phenotype. The pim-1 kinase may be an important intermediate in transmembrane signaling or response phenotype induced by IL-3, GM-CSF and other cytokines whose receptors are structurally similar. Its constitutive expression in some myeloid leukemia cell lines suggests activation of signal cascades utilized by myeloid growth factors.

Cell Division↗

PubMed1992

Stimulatory effect of tumor necrosis factor-alpha on the growth of CMK, a human megakaryoblastic leukemia cell line.

Recombinant human tumor necrosis factor-alpha (TNF-alpha) was found to stimulate the growth of CMK, a human megakaryoblastic leukemia cell line. This stimulatory effect of TNF-alpha was blocked by anti-TNF-alpha antibody, but antibodies to recombinant human interleukin 3, granulocyte-macrophage colony-stimulating factor and interleukin 6 (all growth factors for CMK cells) did not reduce the stimulatory effect of TNF-alpha. Scatchard analysis showed that CMK cells expressed TNF-alpha receptors on the cell surface. The growth of CMK cells was also stimulated by lymphotoxin, which shares the same receptor as TNF-alpha. These results suggest that TNF-alpha stimulated the growth of CMK cells directly via its specific receptor.

Antibodies↗

PubMed1992

IL-3 stimulated haemopoietic stem cell proliferation: evidence for G protein independent mitogenic signalling events.

Interleukin-3 stimulates the survival and proliferation of the FDCP-Mix 1 multipotent stem cell line. We have investigated the possible involvement of a guanyl nucleotide regulatory (G) protein(s) in the IL-3 stimulated proliferative response. We report here that pertussis toxin (PT) can partially inhibit IL-3 stimulated DNA synthesis and that this inhibition is bypassed by TPA. The ADP-ribosylation of the PT substrate G protein in vivo is complete in 2 hours without concomitant inhibition of IL-3 stimulated hexose transport or Na+/H+ exchange. When loaded into FDCP-Mix 1 cells fluoroaluminate and GTP-gamma-S, which can directly activate G proteins, are not capable of mimicking the effects of IL-3. Evidence is also presented that IL-3 does not stimulate a membrane-bound high affinity GTPase activity in the FDCP-Mix 1 cell line. These data suggest that a PT substrate G protein(s) can influence the IL-3 signalling cascade in an indirect or permissive manner, but that the IL-3 receptor does not directly couple to a PT substrate G protein.

Biological Transport↗

PubMed1992

A monoclonal antibody to a novel surface antigen, MKW, blocks the antiproliferative and differentiation effects of granulocyte-macrophagecolony-stimulating factor and vitamin D3.

A monoclonal antibody (MoAb) recognizes a novel 52-Kd cell protein (MKW) that is expressed on cells of the normal myelocytic and monocytic lineage, a subset of B cells, and the U937 cell line. Using the U937 cell line as a model, the MoAb (anti-MKW) was examined for its ability to inhibit the effects of differentiation-inducing factors. In the U937 cell line, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) inhibits cell proliferation, 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits proliferation and induces the early differentiation antigen CD11b, and vitamin D3 inhibits proliferation and induces both CD11b and the late differentiation antigen CD14. The antiproliferative and differentiation effects of rhGM-CSF and vitamin D3 on U937 cells were inhibited by the anti-MKW MoAb. Similar effects were seen when anti-MKW antibody was added 30 minutes before or 2 hours after rhGM-CSF or vitamin D3, suggesting that its effects are not mediated by blocking or binding to the receptors for these growth factors. The anti-MKW MoAb had no effect on TPA-induced differentiation in U937 cells, indicating that TPA exerts its effects through a pathway different from rhGM-CSF and vitamin D3. These results suggest that the MKW antigen is important in controlling the proliferation and differentiation of monocytic cells.

Antibodies, Monoclonal↗

PubMed1992

Colony-stimulating factor (CSF)-dependent growth of two leukemia cell lines.

The progressive accumulation of leukemic cells in acute myeloblastic leukemia (AML) results from the self-renewal capacity of leukemic blast progenitors. The growth of leukemic blast progenitors is supported by growth factors and colony-stimulating factors (CSFs) have been shown to stimulate this phenomenon in vitro. After repeated subculture of leukemic cells obtained from a patient with AML M4 in the presence of recombinant G-CSF, a cell line dependent on G-CSF was established. This cell line, designated OCI/AML1a, does not respond to GM-CSF, interleukin-3 (IL-3), IL-1 or stem cell factor as well as G-CSF. The stimulatory effect of G-CSF on OCI/AML1a cells is almost completely blocked by monoclonal anti-G-CSF antibody. With G-CSF added in the culture, the OCI/AML1a cell line has been growing exponentially for over 5 years now. Another cell line, with growth dependent on IL-3, has also been established from a patient with chronic lymphocytic leukemia in the acute phase. This cell line TMD2 does not respond to G-CSF, GM-CSF, IL-1, or stem cell factor and anti-IL-3-antibody blocks the stimulatory effect of IL-3 on these cells. Receptors for IL-3 have been found on the surface of TMD2 cells. Although the TMD2 cell line is not derived from AML, the novel character of IL-3-dependency provides useful information for the study of the role of growth factor(s) in leukemic cell proliferation. These two CSF-dependent cell lines are expected to be excellent models for the investigation of the precise mechanism by which G-CSF and IL-3 stimulate the growth of leukemic cells.

Aged↗

PubMed1992

Cytokine production by murine cells activated by erythrogenic toxin type A superantigen of Streptococcus pyogenes.

The mode of pathogenic action of the Steptococcus pyogenes superantigen erythrogenic toxin type A (ETA) in causing toxic shock-like syndrome in humans is thought to be mediated by massive release of cytokines by patients immune cells. The cytokine-inducing capacity of ETA as an extracellular protein was compared with that of lipopolysaccharide (LPS), a component of cell wall of gram-negative bacteria. Peritoneal macrophages and splenocytes of BALB/c and C3H/HeJ mice were stimulated by ETA and LPS. Tumor necrosis factor (TNF), interleukin 3 (IL-3) and interleukin 6 (IL-6) activities in the supernatants of stimulated cells were evaluated. In contrast to LPS, ETA induced only low amounts of IL-6 and no detectable TNF activities in peritoneal macrophage supernatants. ETA-triggered BALB/c and C3H/HeJ splenocytes produced great amounts of IL-6. ETA triggered the production of IL-3 by both mice strains splenocytes in a dose dependent manner. The amounts of IL-3 in supernatants were comparable to those induced by concanavalin A. The simultaneous presence of ETA and LPS in macrophage and splenocyte cultures induced a slight enhancement above an additive value after 72-96 h. Challenge of BALB/c mice with ETA 6 h before the harvest of peritoneal macrophages led to an enhanced production of IL-6 upon stimulation with ETA as well as with LPS. Splenocytes of nude BALB/c mice did not produce IL-6 upon stimulation with ETA, whereas LPS-induced IL-6 production was similar in these mice and in their littermates. The pathogenic effect of ETA on host's immune cells could most likely be explained as a consequence of T cell activation. The results confirm also that LPS- and ETA-induced shock is mediated by different cell types.

Animals↗