Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro activation of human granulocytes leads to altered expression of distinct surface antigens. Compared with the changes observed with classic activating reagents such as the phorbol ester PMA similar, but less pronounced alterations of surface antigen expression were observed upon granulocyte activation with human recombinant granulocyte-macrophage colony-stimulating factor (hrGM-CSF). In particular, stimulation with hrGM-CSF is followed by an enhanced expression of the complement receptors CD35 (CR1) and CD11b (CR3) while the low affinity Fc-gamma receptor CD16 (FcRIII) is downregulated. In order to investigate whether there are similar effects under in vivo conditions, we studied the granulocytes from patients undergoing rhGM-CSF therapy before, during, and after treatment. We found a marked increase in CD35 (CR1) and CD11b (CR3) expression and a substantial decrease or even loss of CD16 (FcRIII) on these granulocytes. These changes correlated well with our in vitro data and occurred extremely rapidly after therapy onset. Furthermore, therapy monitoring using ratios calculated by the mean fluorescence channel numbers of CR and FcRIII stainings may combine the advantage of high sensitivity with high reproducibility as a result of the contrasting change in CR and FcRIII expression during granulocyte activation. Being nonparametric values, such ratios are not influenced by individual flow cytometry standardization. Taken together, these activation-associated changes of surface receptor expression and especially of CR over FcRIII ratios are useful parameters for monitoring the in vivo effects of rhGM-CSF.
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PMID:Ratio of complement receptor over Fc-receptor III expression: a sensitive parameter to monitor granulocyte-macrophage colony-stimulating factor effects on neutrophils. 182 39

Polymorphonuclear leukocytes (PMN) constitutively synthesize various plasma membrane proteins including CR1(3) (CD35), CR3 (or Mac-1) alpha-chain (CD11b) and MHC class I. PMN are also able to up-regulate rapidly the expression of CR1 and CR3 to the plasma membrane in response to agonists such as FMLP. To determine whether constitutive PMN translation was static or up-regulatable, PMN were cultured in the presence or absence of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) for 8 h. CR1, CR3 and class I proteins immunoprecipitated from lysates of 35S-methionine pulse-labeled PMN were resolved by SDS-PAGE, fluorographed and quantified by densitometry. GM-CSF-treated PMN synthesized 4.5-fold more class I protein, 3.7-fold more CR1, 2.4-fold more CD11b and 3.4-fold more CR3 beta-chain (CD18), compared with untreated control cells. Actinomycin D treatment of replicate samples of PMN decreased the amount of these proteins synthesized by each group of PMN from 30 to 90%, implying that continued translation was required for the increases in protein synthesis. Nascent CR and class I proteins were inserted into the plasma membrane of PMN, thereby supplementing the molecules already expressed on the cell surface. In addition to these longer term effects of GM-CSF, we observed its acute up-regulatory effects on PMN. GM-CSF induced a five- to 12-fold increase in the expression of CR1 and CR3 on the PMN cell surface within 30 min. These increases were both dose- and time-dependent with maximum up-regulation occurring at 25 pM and at 30 min. In contrast to the long term biosynthetic events, this rapid up-regulation was not dependent on protein synthesis but was due instead to mobilization of CR from intracellular compartments similar to those up-regulated by FMLP. These results demonstrate that PMN can respond to microenvironmental stimuli such as GM-CSF both by rapidly up-regulating and increasing translation and expression of functionally important plasma membrane proteins.
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PMID:Granulocyte-macrophage colony-stimulating factor increases synthesis and expression of CR1 and CR3 by human peripheral blood neutrophils. 197 99

Interleukin 2 (IL-2) administration is known to induce marked eosinophilia. To evaluate the potential role of eosinophils as anti-tumor effectors and to understand the direct or indirect effects of IL-2 on eosinophils, the physical and functional characteristics of eosinophils obtained during IL-2 therapy were compared with those of eosinophils obtained from the same patients before IL-2 administration, or from healthy donors. The treatment schedule consisted of subcutaneous (s.c.) injections of IL-2, and was performed in 7 patients with small-cell lung cancer (SCLC) in advanced stage. A marked increase of hypodense cells in peripheral blood was found to correlate with eosinophil activation in patients undergoing IL-2 therapy. Cytotoxic activity of eosinophils against allogeneic tumor cells (SCLC, K562 and melanoma lines), as assessed by direct and antibody (Ab)-dependent cellular cytotoxicity (ADCC), was markedly increased during IL-2 therapy. Conversely, eosinophils obtained before treatment, like those of healthy donors, lacked any activity against tumor cells. Sera from IL-2-treated, but not from untreated, patients, significantly improved the in vitro survival and anti-tumor cytotoxicity of eosinophils from healthy donors. Comparable effects were obtained with eosinophils cultured with interleukin 5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF) and, to a lesser extent, by tumor necrosis factor-alpha (TNF alpha), while no direct activity was mediated by IL-2. A 91% inhibition of eosinophil ADCC was found after pre-incubation of the sera of IL-2-treated patients with anti-IL-5 but not with anti-GM-CSF or anti-TNF alpha Ab. IL-5 mRNA expression was detected in peripheral-blood lymphocytes (PBL) obtained 4 hr after IL-2 injection during the second and third week of IL-2 therapy. Phenotypic analysis of eosinophils from IL-2-treated patients showed enhanced expression of activation markers, including Fc gamma RII (CD32), HLA-DR, CR3 (CD11b) and CRI (CD35). These findings suggest that a significant cytotoxicity against tumor cells can be mediated by eosinophils after indirect, IL-5-mediated in vivo activation by IL-2, and that eosinophils may be involved in the anti-tumor response(s) induced in vivo by IL-2.
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PMID:In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5. 838 11

We have previously shown that tumor necrosis factor (TNF)alpha strongly potentiates the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-3-dependent proliferation of CD34+ hematopoietic progenitor cells (HPC) through the recruitment of early progenitors with high proliferative potential. Furthermore, the combination of GM-CSF and TNFalpha allows the generation of large numbers of dendritic/Langerhans cells (D-Lc). Herein, we analyzed whether IL-3, when combined to TNFalpha would, as does GM-CSF, allow the generation of CD1a+ D-Lc. Accordingly, cultures of cord blood CD34+ HPC with IL-3 + TNFalpha yielded 20% to 60% CD14+ cells and 11% to 17% CD1a+ cells, while IL-3 alone did not generate significant numbers of CD1a+ cells. Although the percentage of CD1a+ cells detected in IL3 + TNFalpha was lower than that observed in GM-CSF + TNFalpha (42% to 78%), the strong growth induced by IL-3 + TNFalpha generated as many CD1a+ cells as did GM-CSF + TNFalpha. The CD14+ and CD1a+ cells generated with IL-3 + TNFalpha are similar to CD14+ and CD1a+ cells generated in GM-CSF alone and GM-CSF + TNFalpha, respectively. CD1a+ cells differed from CD14+ cells by (1) dendritic morphology, (2) higher expression of CD1a, CD1c, CD4, CD40, adhesion molecules (CD11c, CD54, CD58), major histocompatibility complex (MHC) class II molecules and CD28 ligands (CD80 and CD86), (3) lack of Fc receptor FcgammaRI (CD64) and complement receptor CR1 (CD35) expression, and (4) stronger induction of allogeneic T-cell proliferation. Thus, in combination with TNFalpha, IL-3 is as potent as GM-CSF for the generation of CD1a+ D-Lc from cord blood CD34+ HPC. The dendritic cell inducing ability of IL-3 may explain why mice with inactivated GM-CSF gene display dendritic cells.
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PMID:Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor cells. 863 Apr 1

Thymic nurse cells are known to interact with T cells and play a role in their functional maturation. However, the role of nurse cells in B cell maturation and differentiation is less well established, especially at extralymphoid sites. To address this issue, nurse-like cell clones from bone marrow and synovial tissue of patients with RA (RA-NLC) were established and characterized. RA-NLC constitutively expressed CD29, CD49c, CD54 (ICAM-1), CD106 (VCAM-1), CD157 (BST-1), and class I MHC molecules, and secreted IL-6, IL-7, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Bone marrow-derived and synovial RA-NLC differed in that the former secreted IL-7 and expressed a greater density of CD157 constitutively and after stimulation with IFNgamma, whereas the latter secreted G-CSF and more IL-6. Stimulation of both bone marrow and synovial RA-NLC induced expression of CD40 and class II MHC, but not CD154 (CD40L) or CD35. RA-NLC rescued peripheral B cells from spontaneous apoptosis and promoted survival of B cells for > 4 wk. B cell survival was blocked by antibodies to CD106 or CD157. RA-NLC also increased Ig production from B cells. After long-term culture (4-6 wk) with RA-NLC, but not alone or with fibroblasts, outgrowth of B cells was observed. All B cell lines derived from these cultures had been transformed by EBV, although the RA-NLC themselves were not infected with EBV. Precursor frequency analysis indicated that approximately 1 in 12,500 peripheral B cells could give rise to these EBV-transformed B cell lines upon coculture with RA-NLC. These results indicate that RA-NLC from bone marrow and synovium have the capacity to rescue B cells from spontaneous apoptosis, facilitate Ig production, and promote the outgrowth of EBV-transformed B lymphoblastoid cells. These findings suggest that RA-NLC may play a role in the local and systemic hyperreactivity of B cells characteristic of rheumatoid arthritis.
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PMID:Nurse-like cells from bone marrow and synovium of patients with rheumatoid arthritis promote survival and enhance function of human B cells. 969 Oct 97

In the present study, we investigated the effects of stem cell factor (SCF) and/or thrombopoietin (TPO) on the cell production by cord blood CD34(+) cells using a serum-deprived liquid culture system. Although SCF alone supported a modest production of neutrophilic cells and a remarkable generation of mast cells, the addition of TPO to the culture containing SCF caused an apparent generation of neutrophilic cells, identified by immunocytochemical staining and flow cytometric analysis. The significant production of neutrophilic cells by SCF and TPO was persistently observed from 2 weeks to 2 to 3 months of culture. The interaction between SCF and TPO on the neutrophilic cell generation was greater than the combined effects of SCF with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The addition of neutralizing antibody against G-CSF or GM-CSF did not influence the SCF + TPO-dependent neutrophilic cell production. A single-cell culture study showed that not only CD34(+)CD38(+) c-kit+ cells but also CD34(+)CD38(-)c-kit+ cells were responsible for the neutrophilic cell generation. In clonal cell cultures, GM progenitors as well as erythroid progenitors and multipotential progenitors expanded in the cultures supplemented with SCF and TPO. The neutrophilic cells grown by SCF + TPO were at myeloblast to band cell stages, and scarcely matured to segmented neutrophils. In addition, the cells generated by SCF + TPO were stained with monoclonal antibodies against myeloperoxidase, elastase, lactoferrin, and CD11b, but they had negligible levels of alkaline phosphatase (ALP) and CD35. The replating of the CD34(-)c-kit-/low CD15(+) cells grown by SCF + TPO into a culture containing SCF + G-CSF permitted both the terminal maturation into segmented cells and the appearance of ALP and CD35. These results indicate the existence of a G-CSF/GM-CSF-independent system of neutrophilic cell production.
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PMID:Neutrophilic cell production by combination of stem cell factor and thrombopoietin from CD34(+) cord blood cells in long-term serum-deprived liquid culture. 988 12