Genomic cloning, characterization, and multilineage growth-promoting activity of human granulocyte-macrophage colony-stimulating factor.

Kaushansky, Kenneth; O׳Hara, Patrick J.; Berkner, Kathleen L.; Segal, Gerald M.; Hagen, Frederick S.; Adamson, John W.

doi:10.1073/pnas.83.10.3101

Cited by 144 publications

(51 citation statements)

References 39 publications

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“…The unique cellular source (activated T cells) of hlL-17 and its capacity to induce the secretion by stromal cells of IL-6, IL-8, and G-CSF seem tailored to contribute to the inducible hematopoiesis observed after antigenic stimulation (1,22). Thus, activated T cells may affect hematopoietic progenitors both directly through the production of IL-3 (23-25), IL-4 (26-28), IL-5 (29-31), and GM-CSF (32,33), as well as indirectly through the secretion of hlL-17. Not only could hlL-17 have a long-term effect on hematopoiesis by inducing G-CSF production, but, through the induction of IL-6 and IL-8 release by stromal cells, it may also participate in the triggering of the acute neutrophilia (18,34) that permits a prompt nonspecific immune response against infectious agents (25,35,36).…”

Section: Resultsmentioning

confidence: 99%

T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.

Fossiez¹,

Djossou²,

Chomarat³

et al. 1996

The Journal of Experimental Medicine

1,363

1,158

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SummaryAnalysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame ofHerpesvirus saimiri. Here we report on the cloning of human , the human counterpart ofmurine IL-17. hlL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4 + T cells. Although devoid of direct effects on cells of hematopoietic origin, hlL-17 and the product of its viral counterpart, Olq.F13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte--colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hlL-17, fibroblasts could sustain the proliferation of CD34 + hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hlL-17 may constitute (a) an early initiator of the T cell-dependent inflammatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis.T lymphocytes produce an array of small proteins that are involved in cell growth, inflammation, immunity, differentiation, and repair. These protein mediators referred to as cytokines are not produced constitutively by T cells, but rather are induced after receptor-mediated T cell activation (1, 2). Murine cytotoxic T lymphocyte associated antigen-8 (mCTLA8) 1, a cDNA previously cloned by lq.ouvier et al. (3) from a T cell subtraction library, displays some of the features ofa cytokine gene: in particular, a pre1Abbreviations used in this paper: hlL-17, human IL-17; HVS, Herpesvirus saimiri; ORF13, open reading frame 13; mCTLA8, murine cytotoxic T lymphocyte-associated antigen 8; PGE 2, prostaglandin E2; PI, PMA and ionomycin.Parts of this work were presented at

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Section: Resultsmentioning

confidence: 99%

T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.

Fossiez¹,

Djossou²,

Chomarat³

et al. 1996

The Journal of Experimental Medicine

1,363

1,158

View full text Add to dashboard Cite

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“…Over the past several years, many of the humoral regulators of erythropoiesis have been identified and molecularly cloned. Although IL-3 (10, 11), GM-CSF (12,13), and c-kit ligand (KL [14]) have been shown to expand early erythroid progenitors, erythropoietin (Epo), which promotes the terminal differentiation of these cells, is thought to be the critical regulator of red cell production ( 15,16).…”

Section: Introductionmentioning

confidence: 99%

Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy.

et al. 1995

Self Cite

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Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production. Several features of c-Mpl expression, including its presence on erythroid cell lines, and the panmyeloid transformation characteristic of myeloproliferative leukemia (MPL) viral disease led us to investigate whether this receptor-ligand system may play a role in erythropoiesis. We report that although TPO alone did not support the growth of either early or late erythroid progenitors, it acted in synergy with erythropoietin to expand these populations. Moreover, while the effects on erythropoiesis in normal animals were modest, TPO greatly expanded the number of erythroid progenitors and blood reticulocytes and was associated with accelerated red cell recovery in myelosuppressed mice. Together, these data strongly suggest that erythroid progenitors respond to TPO and that this newly cloned cytokine, critical for platelet production, can augment erythropoiesis in states of marrow failure. (J. Clin. Invest. 1995. 96:1683-1687

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“…With this tool, the existence of several positive, though not necessarily lineage specific, growth-enhancing molecules has been demonstrated. Such proliferation and/or maturation promoting activities include megakaryocyte colony-stimulating factor (Meg-CSF)l (2), granulocyte-macrophage colony-stimulating factor (GM-CSF) (3), IL 3 (4), thrombopoietin (TPO) (5,6), megakaryocyte stimulatory factor (MSF) (7,8), and erythropoietin (9).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide.

Gewirtz¹,

Calabretta²,

Rucinski³

et al. 1989

J. Clin. Invest.

140

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We report that highly purified human platelet factor 4 (PF4) inhibits human megakaryocytopoiesis in vitro. At 2 25 gg/ml, PF4 inhibited megakaryocyte colony formation -80% in unstimulated cultures, and -58% in cultures containing recombinant human IL 3 and granulocyte-macrophage colony-stimulating factor. Because PF4 (25 gg/ml) had no effect on either myeloid or erythroid colony formation lineage specificity of this effect was suggested. A synthetic COOH-terminal PF4 peptide of 24, but not 13 residues, also inhibited megakaryocyte colony formation, whereas a synthetic 18-residue fithromboglobulin (,f-TG) peptide and native fl-TG had no such effect when assayed at similar concentrations. The mechanism of PF4-mediated inhibition was investigated. First, we enumerated total cell number, and examined cell maturation in control colonies (n = 200) and colonies (n = 100) that arose in PF4-containing cultures. Total cells per colony did not differ dramatically in the two groups (6.1±3.0 vs. 4.2±1.6, respectively), but the numbers of mature large cells per colony was significantly decreased in the presence of PF4 when compared with controls (1.6±1.5 vs. 3.9±2.3; P < 0.001). Second, by using the human leukemia cell line HEL as a model for primitive megakaryocytic cells, we studied the effect of PF4 on cell doubling time, on the expression of both growth-regulated (H3, p53, c-myc, and c-myb), and non-growth-regulated (fi2-microglobulin) genes. At high concentrations of native PF4 (50 ,gg/ml), no effect on cell doubling time, or H3 or p53 expression was discerned. In contrast, c-myc and c-myb were both upregulated. These results suggested the PF4 inhibited colony formation by impeding cell maturation, as opposed to cell proliferation, perhaps by inducing expression of c-myc and c-myb.The ability of PF4 to inhibit a normal cell maturation function was then tested. Megakaryocytes were incubated in synthetic PF4, or ,B-TG peptides for 18 h and effect on Factor V steadystate mRNA levels was determined in 600 individual cells by in situ hybridization. fl-TG peptide had no effect on FV mRNA levels, whereas a -60% decrease in expression of Factor V mRNA was found in megakaryocytes exposed to 2 100 ng/ml synthetic COOH-terminal PF4 peptide. Accordingly, PF4 modulates megakaryocyte maturation in vitro, and may funcAddress reprint requests to Dr.

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Genomic cloning, characterization, and multilineage growth-promoting activity of human granulocyte-macrophage colony-stimulating factor.

Cited by 144 publications

References 39 publications

T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.

T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.

Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy.

Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide.

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