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PubMed2005

Activation of purified allogeneic CD4(+) T cells by rat bone marrow-derived dendritic cells induces concurrent secretion of IFN-gamma, IL-4, and IL-10.

Dendritic cells (DCs) are highly specialized antigen-presenting cells that play a key role in the initiation and regulation of immune responses. The ability of DCs to process antigens and the outcome of their interaction with T cells are largely dependent on phenotype as well as maturation state of DCs. In this study, we generated DCs from rat bone marrow precursors. Bone marrow cells cultured in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and Flt-3 ligand (FL) produced immature DCs that expressed intermediate levels of major histocompatibility complex (MHC) class II, low levels of CD80 and CD86 molecules and displayed a high capacity of endocytosis. Bone marrow-derived DCs (BMDCs) matured in the presence of lipopolysaccharide (LPS) upregulated expression of MHC class II, CD80 and CD86, while their phagocytic capacity was dramatically reduced. Mature BMDCs stimulated vigorous proliferation of purified allogeneic CD4(+) T cells in a primary mixed leukocyte reaction (MLR) and elicited a mixed cytokine profile in allogeneic CD4(+) T cells: DCs activated CD4(+) T cells to produce interferon (IFN)-gamma, IL-4, and IL-10. Thus, rat BMDCs effectively internalize antigens and stimulate T cell proliferation but fail to induce an unidirectional polarization of T helper (T(H)) cells and in this respect differ from both human and mouse DCs.

Animals↗
PubMed2002

Tumor necrosis factor-alpha inhibits generation of glycophorin A+ cells by CD34+ cells.

OBJECTIVE: The inhibitory effects of tumor necrosis factor-alpha (TNF-alpha) on cytokine-induced proliferation and differentiation of normal human erythroid progenitors have been characterized extensively, yet little is known about the maturation level of erythroid progenitors that are sensitive to TNF-alpha or of the expression of TNF receptors (TNFRs) in erythroid lineage. The aim of this study was to determine the extent to which human erythroid progenitor cells are sensitive to TNF-alpha, and to relate this to the expression of TNFRs in the erythroid lineage. MATERIALS AND METHODS: Highly purified human CD34+ cells underwent erythroid differentiation, with or without TNF-alpha. We used colony assay as well as a method by which colony-forming unit-erythroid (CFU-E) and glycophorin A (GPA; a specific marker for erythroid lineage) positive cells can be generated in liquid phase from purified human CD34+ cells in the presence of multiple cytokines, including stem cell factor (SCF), interleukin-3 (IL-3), and erythropoietin (EPO). During erythroid differentiation of CD34+ cells, TNFRs expression were monitored. RESULTS: TNF-alpha inhibited the generation of GPA+ cells by CD34+ cells as well as the proliferative capacity of GPA+ cells supported by EPO, IL-3, and SCF. Erythroid progenitors became resistant to the inhibitory effect of TNF-alpha as they matured. The detectable expression of TNFR-I was transient in the early phase of erythroid differentiation, whereas TNFR-II was expressed through the entire course of erythroid differentiation of CD34+ cells. CONCLUSIONS: TNF-alpha suppresses erythropoiesis by inhibiting the generation of GPA+ cells derived from CD34+ cells as well as by inhibiting the proliferative capacity of GPA+ cells. Although the presence of TNFRs does not directly indicate that the receptor(s) mediates death signaling, altered expression of TNFRs depending on the level of maturation may imply altered sensitivities to TNF-alpha in various stage of erythroid progenitors.

Adult↗
PubMed1999

Long-term bone marrow cultures in Diamond-Blackfan anemia reveal a defect of both granulomacrophage and erythroid progenitors.

The hematopoietic defect of Diamond-Blackfan anemia (DBA) results in selective failure of erythropoiesis. Thus far, it is not known whether this defect originates from an intrinsic impediment of hematopoietic progenitors to move forward along the erythroid pathway or to the impaired capacity of the bone marrow (BM) microenvironment to support proliferation and differentiation of hematopoietic cells. Reduced longevity of long-term bone marrow cultures, the most physiologic in vitro system to study the interactions of hematopoietic progenitors and hematopoietic microenvironment, is consistent with a defect of an early hematopoietic progenitor in DBA. However, stromal adherent layers from DBA patients generated in a long-term culture system, the in vitro counterpart of BM microenvironment, did not show evidence of any morphologic, phenotypic, or functional abnormality. Our major finding was an impaired capacity of enriched CD34+ BM cell fraction from DBA patients, cultured in the presence of normal BM stromal cells, to proliferate and differentiate along the erythroid pathway. A similar impairment was observed in some DBA patients along the granulomacrophage pathway. Our result points to an intrinsic defect of a hematopoietic progenitor with bilineage potential that is earlier than previously suspected as a relevant pathogenetic mechanism of the disease. The finding of impaired granulopoiesis in some DBA patients underlines the heterogeneity of this rare disorder.

Adolescent↗
PubMed2004

Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3).

The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans. The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors. Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor. To gain insight into the biologic function of another member of the PLSCR family, we investigated mice with targeted deletion of PLSCR3, a protein that like PLSCR1 is expressed in many blood cells but which, by contrast to PLSCR1, is also highly expressed in fat and muscle. PLSCR3(-/-) mice at 2 months of age displayed aberrant accumulation of abdominal fat when maintained on standard rodent chow, which was accompanied by insulin resistance, glucose intolerance, and dyslipidemia. Primary adipocytes and cultured bone-marrow-derived macrophages from PLSCR3(-/-) mice were engorged with neutral lipid, and adipocytes displayed defective responses to exogenous insulin. Plasma of PLSCR3(-/-) mice was elevated in non-high-density lipoproteins, cholesterol, triglycerides, nonesterified fatty acids, and leptin, whereas adiponectin was low. These data suggest that the expression of PLSCR3 may be required for normal adipocyte and/or macrophage maturation or function and raise the possibility that deletions or mutations affecting the PLSCR3(-/-) gene locus may contribute to the risk for lipid-related disorders in humans.

Adiponectin↗
PubMed2004

Interleukin-4 selectively inhibits interleukin-2 secretion by lipopolysaccharide-activated dendritic cells.

Dendritic cells (DCs) generated in vitro from bone marrow precursors using granulocyte-macrophage colony-stimulating factor (GM-CSF) secrete interleukin-2 (IL-2) upon activation, an event probably associated to the initiation of adaptive immune responses. Additionally, they produce IL-12, a cytokine related to T-cell polarization. To analyse the effect of IL-4 on DC differentiation and function, we assessed the capacity of murine bone marrow dendritic cells (BMDCs) differentiated with GM-CSF in the presence or absence of IL-4 to produce IL-2 and IL-12 upon lipopolysaccharide (LPS) activation. We found that although IL-4 enhanced DC IL-12p70 production, it strongly impaired IL-2 secretion by BMDCs. This inhibition, which depends on the presence of IL-4 during LPS activation, is DC specific, as IL-4 did not affect IL-2 secretion by T cells. Interestingly, inhibition of DC IL-2 production did not prevent DC priming of T lymphocytes. These results illustrate a new putative role for IL-4 on the regulation of the immune response and should help clarify the controversial reports on the effect of IL-4 on DCs.

Animals↗
PubMed1993

Inhomogeneity of the circulating BFU-E regulation in sickle cell anaemia: accessory cells properties and BFU-E growth factor response pattern.

Sickle cell anaemia (SS) patients with low (< 9%) HbF levels (LFSS) are characterized by an increased number of circulating BFU-E in active DNA synthesis, and release of burst promoting activity (BPA) by unstimulated low density (LD) adherent cells. In contrast, circulating BFU-E from SS patients with high (> 9%) HbF levels (HFSS) are normal in number, largely in resting phase, and their LD cells do not release BPA-like activity. We report now that in LFSS patients, adherent cell depletion decreases BFU-E growth in culture and apparent BFU-E cycling. Furthermore, addition of conditioned media (CM) from LD cells of LFSS patients restored cycling BFU-E expression in culture. Neutralization analysis with anti-GM-CSF antibody demonstrated that GM-CSF is, at least, one factor responsible for BPA activity present in this CM. Thus, GM-CSF is constitutively produced by unstimulated monocytes in LFSS patients. In contrast, HFSS patients' adherent cell depletion increases cycling of BFU-E in culture. CM from HFSS patients inhibits BFU-E expression in culture. Hence, LD adherent cells from HFSS patients may release a yet unknown inhibitor factor(s). In addition, we report a distinct response pattern in SS patients' BFU-E to growth factor (GM-CSF, IL-3): (a) LFSS patients have a BFU-E population, equally responsive to GM-CSF and IL-3; (b) HFSS patients, have a subset of BFU-E exclusively dependent on IL-3 (20-40% of the circulating BFU-E). This pattern is very similar to that of normal BFU-E. In conclusion, BFU-E from LFSS patients represent an actively proliferating population, equally responsive to GM-CSF and IL-3, controlled by constitutively produced GM-CSF, suggesting a unique BFU-E behaviour in SS patients with low HbF levels and high haemopoietic stress. The heterogeneous regulation of BFU-E in SS disease seems to be the epiphenomenon of HbF levels, and not vice versa.

Adult↗
PubMed1994

In vitro growth of human fetal CD34+ cells in the presence of various combinations of recombinant cytokines under serum-free culture conditions.

CD34+ cells were purified from midtrimester human fetal blood and adult bone marrow samples and seeded in serum-free fibrin-clot cultures in order to evaluate the number and the responsiveness to recombinant cytokines of pluripotent (CFU-GEMM), erythroid (BFU-E), megakaryocyte (BFU-meg and CFU-meg) and granulocyte/macrophage (CFU-GM) haemopoietic progenitor cells. The number of the different haemopoietic progenitors/1 x 10(3) CD34+ cells, except CFU-meg, was significantly higher in fetal blood than in adult bone marrow in cultures stimulated by any combination of cytokines including interleukin-3 (IL-3), granulocyte/macrophage colony stimulating factor (GM-CSF) or stem cell factor (SCF) plus erythropoietin (Epo). Nevertheless, whereas adult BFU-E showed a maximal growth in the presence of Epo plus IL-3 or Epo plus SCF, fetal BFU-E showed an optimal growth in the presence of Epo alone, the sensitivity of fetal BFU-E to suboptimal concentrations of Epo being approximately 10-15-fold higher than that of adult BFU-E. Addition of optimal concentrations of IL-3, GM-CSF or SCF, alone or in various combinations, to Epo-containing cultures induced a significant increase in both the number and size of fetal CFU-GEMM, and CFU-GM, and a parallel decrease of fetal BFU-E. Finally, SCF potently synergized with IL-3 in increasing the growth of both classes of fetal megakaryocyte progenitors, BFU-meg and CFU-meg.

Adult↗
PubMed1994

Circulating cytokines in sickle cell patients during steady state.

Plasma levels of GM-CSF, IL-3, IL-6 and IL-1 (alpha,beta) were investigated in steady-state sickle cell patients. We find that SS patients with low levels of HbF (< 9% [LFSS]) are characterized by elevated plasma GM-CSF, whereas in patients with high levels of HbF (HFSS), GM-CSF is not detectable. In contrast, HFSS patients exhibited increased plasma IL-3 (m = 84.8 +/- 57 pg/ml), whereas LFSS patients had lower or no detectable plasma IL-3, IL-1(alpha,beta) and IL-6 were also detected in plasma from some SS patients, but there was no correlation with HbF levels. Normal controls tested negative for all cytokines, except for one individual positive for IL-3. These results are compatible with a model in which the level of haemopoietic stress determines the level of participation of GM-CSF or IL-3 in the regulation of SS circulating BFU-E.

Adult↗
PubMed1999

Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS).

The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing's sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing's sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.

3T3 Cells↗
PubMed2001

Receptor binding cancer antigen expressed on SiSo cells, a novel regulator of apoptosis of erythroid progenitor cells.

To better understand the control of apoptosis during erythropoiesis, this study investigated the role of a novel tumor-associated antigen, RCAS1 (receptor binding cancer antigen expressed on SiSo cells), with regard to the regulation of apoptosis of erythroid progenitor cells. Erythroid colony-forming cells (ECFCs) purified from human peripheral blood were used. Binding experiments of RCAS1 showed that ECFCs abundantly expressed receptors (RCAS1R) for RCAS1 and that the degree of binding of RCAS1 to the receptors diminished rapidly during erythroid maturation in vitro. When the soluble form of RCAS1 was added to the cultures, ECFCs underwent apoptosis, including collapse of the mitochondrial transmembrane potential, and activation of caspases 8 and 3. The addition of an anti-Fas blocking antibody or Fas-Fc failed to reduce the apoptosis induced by RCAS1, thereby indicating that effects of RCAS1 are independent of Fas activation. When binding of RCAS1 to normal bone marrow cells was analyzed, RCAS1R was evident on cells with an immature erythroid phenotype (transferrin receptor(+)/glycophorin A(-)) but not with a mature phenotype (transferrin receptor(-)/glycophorin A(+)). Histochemical staining revealed the expression of RCAS1 in the cytoplasm of bone marrow macrophages. These findings indicate that RCAS1, which is mainly produced by macrophages in hematopoietic tissue, may have a crucial role in controlling erythropoiesis by modulating apoptosis of erythroid progenitor cells via a Fas-independent mechanism.

Adenocarcinoma↗
PubMed2006

Extra-adrenal myelolipoma in the renal hilum: a case report and review of the literature.

Myelolipoma most commonly arises in the adrenal gland. Extra-adrenal myelolipomas are rare; to our knowledge, approximately 37 previous cases have been reported. We report a myelolipoma presenting as a localized mass in perirenal adipose tissue juxtaposed to the renal hilum in a 65-year-old Caucasian man who presented with back pain, weight loss, hematuria, and flank pain. The most likely diagnostic considerations were pyelonephritis or primary renal malignancy. However, histology revealed mainly mature adipose tissue along with multiple scattered islands of hematopoietic precursor cells. Representation of all the three hematopoietic cell lineages (granulocytic, erythroid, and megakaryocytic) was present. Perirenal masses such as morphologically identified myelolipomas are rarely, if ever, considered in differential diagnosis. The purpose of this report is to elicit consideration of extra-adrenal myelolipoma when formulating a differential diagnosis for perirenal and retroperitoneal tumors. Although primary and secondary malignant retroperitoneal tumors are much more common and aggressive neoplasms, establishing the correct diagnosis has important therapeutic and prognostic implications.

Adipose Tissue↗
PubMed2001

[The study of low dose radiation inducing hormesis effect on hematopoietic system].

OBJECTIVE: To study the hormesis effect on hematopoietic system induced by low dose radiation. METHOD: CFU-GM and BFU-E were cultured in methylcellulose semi-solid culture system, levels of GM-CSF and IL-3 were assayed by ELISA and mRNA levels of GM-CSF, G-CSF, IL-3 by in situ hybridization, narrow line hybridization and Northern blot. RESULTS: (1) The in vitro yields of CFU-GM and BFU-E from radiated mice was higher than that from the control. (2) The serum protein level of GM-CSF increased obviously than that of controls; (3) mRNA levels of GM-CSF and G-CSF were also increased. CONCLUSION: There is hormesis effect on hematopoietic system induced by low dose radiation, which may be related to the increasing of cytokines.

Animals↗
PubMed2003

[Effect of angiotensin II on cord blood CD34(+) cells expansion in vitro].

Angiotensin II (Ang II) is one active substance of renin-angiotensin system. In order to explore the effect of Ang II combined with various cytokines on proliferation and differentiation of cord blood CD34(+) cells, in vitro experiments of cell cultures of Ang II with or without cytokines were taken place. The results showed that Ang II stimulated both BFU-E and CFU-GM expansion. The numbers of BFU-E and CFU-GM raised with increase of Ang II concentrations ranged from 0.01 - 0.1 micro mol/L. In semi-solid culture assay, Ang II stimulated CFU-GM production but no effect on BFU-E occurred. The multiple number of CFU-GM increased from 2.3 +/- 0.8 to 7.8 +/- 1.9 times when Ang II was added into SCF + G-CSF + GM-CSF + IL-3 combination. Similarly, the multiple number of BFU-E increased from 3.1 +/- 1.8 to 9.2 +/- 2.3 times when Ang II was combined with SCF + EPO + TPO + IL-3. In conclusion, Ang II stimulated cord blood hematopoietic stem/progenitor cell expansion in vitro the in presence of various cytokines.

Angiotensin II↗
PubMed1992

Implantation and maintenance of functional human bone marrow in SCID-hu mice.

Human fetal bone fragments implanted in the immunodeficient C.B-17 scid/scid (SCID) mouse were shown to sustain active human hematopoiesis in vivo. Human progenitor cell activity was maintained for as long as 20 weeks after implantation and was associated with multilineage differentiation in the engrafted bone. Thus, the bone implants provided stem cells as well as the microenvironment requisite for their long-term maintenance and multilineage differentiation. Administration of human erythropoietin (Epo) stimulated human erythropoiesis in human bone implants. This animal model may facilitate direct analysis of a wide variety of physiologic and pathologic conditions of human bone marrow (BM) in vivo.

Animals↗
PubMedDate not supplied

Alterations in hematopoietic responses in B6C3F1 mice caused by drinking a mixture of 25 groundwater contaminants.

Myelotoxicity parameters were monitored in female B6C3F1 mice exposed to 0, 1, 5, and 10% of a chemical mixture stock in drinking water for 2.5 to 31.5 weeks. The mixture consisted of 25 groundwater contaminants frequently found near toxic waste dumps, as determined by U.S. Environmental Protection Agency (EPA) surveys. Water consumption, body and organ weights, and hematological and histopathological examinations were conducted. No animals developed overt signs of toxicity after 2.5 weeks of treatment. No significant effect on bone marrow cellularity was observed after 2.5, 15.5, or 31.5 weeks of exposure; however, mice exposed to 5% or higher concentrations of the chemical mixture stock solution for 15.5 weeks showed significant suppression of granulocyte-macrophage progenitor cells (CFU-GM) and erythroid precursors (CFU-E) with no changes in body weight, histopathological or hematological parameters. Decreases occurred in erythrocyte mean corpuscular volume of mice exposed to a 10% solution for 15.5 weeks and to 5 and 10% solutions following 31.5 weeks of treatment. In addition, dose-related decreases were found in body, liver, and thymus weights in the 5 and 10% solutions exposure groups after 31.5 weeks. These results suggest that bone marrow may be a sensitive indicator for long-term, low-level exposure of multiple chemicals in mice. Furthermore, long-term exposure to highly contaminated groundwater may present a subtle risk to the hematopoietic system.

Animals↗