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C Selleri

Publications and source records attributed to C Selleri.

At least 55 records · Page 3Linked to original sources
PubMed1995

Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1.

Biologic responses to cytokines are mediated by intracellular pathways involving induction of signaling and metabolic cascades. Interferon (IFN) regulatory factor-1 (IRF-1) is a major transcription factor induced not only by IFN-gamma but also by other cytokines including tumor necrosis factor-alpha (TNF-alpha). Possible IRF-1 binding sequence elements have been located in the promoter regions of several genes, including p53, inducible nitric oxide synthase, and cyclin D1. IFN-gamma and TNF-alpha can inhibit hematopoiesis in vitro and have been implicated in the pathophysiology of bone marrow (BM) failure. We investigated whether the inhibitory effects of these cytokines were intracellularly mediated through the expression of IRF-1 or -2 in target cells. In total BM cells, IRF-1 mRNA expression increased after stimulation with IFN-gamma and TNF-alpha; the stronger effect was observed with IFN-gamma. In contrast, IRF-2 mRNA expression was constitutive and not altered by cytokine stimulation. By gene amplification, low levels of IRF-1 mRNA were present in unstimulated, highly purified CD34+ cells; on exposure to IFN-gamma and TNF-alpha, amplified IRF-1 mRNA showed a much stronger signal than control. When CD34+ cells were treated with IFN-gamma and TNF-alpha, IRF-1 antisense oligodeoxynucleotide (ODN) partially reversed the suppressive effects on CD34+ cell-derived colony formation by IFN-gamma but not those by TNF-alpha. In parallel experiments, IRF-1 antisense ODN decreased both IRF-1 protein and mRNA expression. The effects of ODN were sequence-specific and concentration-dependent. These results suggest that the inhibitory hematopoietic effects of IFN-gamma and TNF-alpha are mediated by different pathways. For IFN-gamma, IRF-1 is involved in the activation of cellular genes responsible for IFN-gamma suppressive effects.

Antigens, CD34↗
PubMed1995

Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro.

Activation of Fas antigen, a cell surface receptor molecule, by its ligand results in transduction of a signal for cell death. The Fas system has been implicated in target cell recognition, clonal development of immune effector cells, and termination of the cellular immune response. Fas antigen expression on lymphocytes is regulated by interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha), cytokines that also have inhibitory effects on hematopoiesis. We investigated Fas antigen expression on human marrow cells and the effects of Fas activation on hematopoiesis in vitro. Freshly isolated immature hematopoietic cells, as defined by the CD34 marker, did not express Fas antigen at levels detectable by fluorescent staining. CD34+ cells, which include progenitors and stem cells, showed low levels of Fas expression in culture, even in the presence of growth factors. Stimulation by TNF alpha and IFN gamma markedly increased Fas antigen expression on CD34+ cells. Anti-Fas antibody, which mimics the action of the putative ligand, enhanced IFN gamma- and TNF alpha-mediated suppression of colony formation by bone marrow (BM) in a dose-dependent manner. This effect did not require the presence of accessory cells. Colony formation from mature (CD34+ CD38+) and immature (CD34+ CD38-) progenitor cells and long-term culture initiating cells were susceptible to the inhibitory action of anti-Fas antibody in the presence of IFN gamma and TNF alpha. Apoptosis assays performed on total BM cells and CD34+ cells showed that anti-Fas antibody induced programmed cell death of CD34+ BM cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1995

Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death.

Increased expression of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in bone marrow failure disorders suggests a possible pathophysiologic role of these cytokines in disease. In this study, we tested the action of TNF-alpha and IFN-gamma on phenotypically and functionally defined stages of hematopoietic development using highly purified progenitor cell populations assayed in standardized culture systems. We hypothesized that the inhibitory effects of IFN-gamma and TNF-alpha might be related to the induction of programmed cell death. In methylcellulose colony assays, IFN-gamma and TNF-alpha inhibited the growth of early hematopoietic cells, including committed CD34+CD38+ progenitor cells and phenotypically less mature CD34+CD38- cells, with 50% decreased colony formation occurring in the range of 750-1,000 U/ml of IFN-gamma and 10-15 ng/ml of TNF-alpha. More potent suppressive effects were observed in cultures supplemented with the combination of both cytokines than in cultures treated with IFN-gamma or TNF-alpha alone. When used at these concentrations, IFN-gamma and TNF-alpha inhibited growth of CD34(+)-enriched long-term culture-initiating cells by 88% and 68%, respectively. IFN-gamma and TNF-alpha triggered apoptosis of total bone marrow and CD34+ cells, recognized by the presence of a characteristic pattern of DNA degradation after low molecular weight DNA extraction, and by detection of apoptotic cells by the in situ terminal deoxynucleotidyl transferase assay. We speculate that chronic exposure of hematopoietic tissue to TNF-alpha and IFN-gamma in vivo may result in broad depletion of the stem and progenitor cell pools. Death of these cells due to apoptosis rather than transient inhibition of proliferation may be responsible for long-lasting hematologic consequences.

ADP-ribosyl Cyclase↗
PubMed1995

Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia.

Fas antigen, a receptor molecule that mediates signals for programmed cell death, is involved in T-cell-mediated killing of malignant, virus-infected or allogeneic target cells. Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), potent inhibitors of haemopoiesis, enhance Fas receptor expression on bone marrow (BM) CD34+ cells, and both cytokines render haemopoietic progenitor cells susceptible to Fas-mediated inhibition of colony formation due to the induction of apoptosis. Haemopoietic suppression in aplastic anaemia (AA) has been associated with aberrant IFN-gamma, increased TNF-beta expression, and elevated numbers of activated cytotoxic T-cells in marrow. We have now examined Fas antigen expression in fresh AA BM samples. In normal individuals few CD34+ cells expressed Fas antigen and normal marrow cells had low sensitivity to Fas-mediated inhibition of colony formation. In contrast, in early AA, BM CD34+ cells showed markedly increased percentages of Fas receptor-expressing CD34+ cells, which correlated with increased sensitivity of AA marrow cells to anti-Fas antibody-mediated inhibition of colony formation. The proportion of Fas antigen-bearing cells was lower in recovered patients' BM. Fas antigen was also detected in the marrow of some patients with myelodysplasia, especially the hypocellular variant. These results are consistent with the hypothesis that AA CD34+ cells, probably including haemopoietic progenitor cells, express high levels of Fas receptor due to in vivo exposure to IFN-gamma and/or TNF-alpha and are suitable targets for T-cell-mediated killing. Our results suggest that the Fas receptor/Fas ligand system are involved in the pathophysiology of BM failure.

Adult↗
PubMed1995

Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha.

IFN-gamma and TNF-alpha, potent inhibitors of hematopoiesis, induce nitric oxide synthase (NOS) in various cell types. When normal human bone marrow (BM) or CD34+ cells were exposed to NO, inhibition of colony formation was dose dependent and direct. NO induced apoptosis in BM progenitors, as shown by electrophoretic detection of DNA degradation and deoxynucleotidyl transferase assay. Using PCR and immunoprecipitation, we found inducible NOS (iNOS) mRNA and iNOS protein in BM after stimulation with IFN-gamma or TNF-alpha. iNOS mRNA was also detected by PCR in highly purified CD34+ cells; TNF-alpha or IFN-gamma increased iNOS expression. The presence of iNOS in CD34+ cells was confirmed in single cells by immunochemical staining. NG-Monomethyl-L-arginine (MM-Arg), an NOS inhibitor, partially reversed the effects of TNF-alpha and, to a lesser extent, IFN-gamma in methylcellulose culture of total BM and CD34+ cells, and inhibited apoptosis of BM cells induced by these cytokines. When the effects of competitive iNOS inhibition were tested on more immature progenitors, MM-Arg increased the number of long-term BM culture-initiating cells in control cultures but failed to protect these cells from the inhibitory action of IFN-gamma and TNF-alpha. Our results suggest that NO may be one mediator of cytokine-induced hematopoietic suppression.

Amino Acid Oxidoreductases↗
PubMed1994

A novel chromosomal abnormality detected in a case of acute myelomonocytic leukemia.

A not yet recorded translocation, t(3:17)(q21;q23), detected in a case of acute myelomonocytic leukemia, is reported. In spite of an aggressive cytotoxic chemotherapy, the disease showed a rapid fatal course, confirming the dismal prognostic significance of structural, 'primary' chromosomal abnormalities in acute leukemias.

Chromosomes, Human, Pair 17↗
PubMed1993

Trisomy 13 in a patient with leukemic progression of myelodysplasia.

Four months after the diagnosis of refractory anemia, a 60-year-old patient developed acute leukemia with blast cells that were poorly differentiated by morphology and clearly myeloid by immunophenotyping. Cytogenetic analysis performed at leukemization showed trisomy 13. An extra copy of chromosome 13 has already been reported in a few cases of acute leukemia and myelodysplastic syndrome.

Anemia, Refractory↗
PubMed1993

Cytoplasmic GpIIb-IIIa and cytokine secretion by blasts in a case of megakaryoblastic transformation of essential thrombocythemia.

A 49-year-old woman with a four year history of therapy resistant essential thrombocythemia, progressed to acute leukemia that also proved refractory to chemotherapy. Blast cell features including immunophenotype, cytogenetics and in vitro cell cultures, suggested megakaryoblastic leukemia. In serum-free culture, blasts released GM-CSF and IL-6 which sustained autocrine growth and promoted normal myeloid and megakaryocytic colony formation.

Antigens, CD↗
PubMed1991

Danazol: in vitro effects on human hemopoiesis and in vivo activity in hypoplastic and myelodysplastic disorders.

We examined the effects of danazol on in vitro growth of human bone marrow and peripheral blood progenitor cells from 15 normal donors and 5 myelodysplastic patients, and on in vivo hemopoiesis in 30 patients with hypoplastic or myelodysplastic disorders. At concentrations similar to that reported as the plasma level after oral administration, danazol significantly increased CFU-GM colony growth in all normal donors, while the influence on CFU-E, BFU-E, CFU-MK and CFU-GEMM colony growth was less evident. The stimulatory effect on CFU-GM was observed even after accessory cell depletion. Np stimulatory effect either in vitro on the growth of all hemopoietic progenitors or in vivo was observed in 15 myelodysplastic patients, while 7 complete and 3 partial hematological responses occurred in 15 patients with hypoplastic disorders. In conclusion, our results suggest that danazol exerts a direct stimulatory activity in vitro at least on CFU-GM, and a hemopoietic stimulatory effect in vivo in hypoplastic but not in myelodysplastic disorders.

Adult↗
PubMed1990

Induction of alkaline phosphatase activity in chronic myeloid leukemia cells: in vitro studies and speculative hypotheses.

Three patients with Ph chromosome + chronic myeloid leukemia (CML) in chronic phase suffered from intercurrent pleuritis of undefined origin. At that time, leucocyte alkaline phosphatase activity (LAPA) score was low for circulating neutrophils, but high for those from pleural effusion. LAP negative circulating CML granulocytes were incubated with the pleural liquid: after 40-70 hr, almost all were intensely LAP positive. This finding suggests that the low LAPA score in resting CML neutrophils is attributable to the absence of appropriate stimuli rather than to an incapacity to synthesize the enzyme.

Alkaline Phosphatase↗