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

Resting natural killer (NK) cells express the p75 chain of the IL-2 receptor (IL-2R beta) and most NK cells express the CD2 (erythrocyte rosette) receptor. The cell adhesion molecule, LFA-3, is a natural co-ligand for CD2. Tac antigen (IL-2R alpha), a p55 IL-2R subunit, can be expressed after NK activation and may play a role in IL-2-induced NK proliferation. Little is known of the molecular mechanisms underlying cytokine production in NK cells. We investigated the roles of IL-2R alpha, IL-2R beta, and CD2/LFA-3 in the molecular regulation of NK cell granulocyte/macrophage-colony-stimulating factor (GM-CSF) production. Enriched populations of peripheral blood NK cells were separated into CD16-positive and CD16-negative fractions by flow cytometry; positively selected cells were greater than 97% positive for CD16 (the FcIII receptor for IgG which is present on almost all NK cells), less than 1% positive for the T cell antigen CD3, and did not demonstrate rearrangement of the T cell receptor beta chain gene by Southern blot. NK cell supernatants were harvested after 3-4 d of incubation with 0-100 U/ml IL-2, or after incubation with anti-CD2 (T11(3] MAb and sheep red blood cells (SRBC are a homologue for LFA-3). Parallel cell aliquots were harvested at 3-16 h for transcriptional run-on assays, S1 nuclease assays, and actinomycin D mRNA t1/2 determinations. IL-2-activated NK supernatants contained large amounts of GM-CSF (178 +/- 35 pg/ml) by ELISA as did supernatants from CD2-activated NK cells (T11(3) MAb + SRBC: 212 +/- 42) vs. less than 20 pg/ml for NK cells incubated alone or with either SRBC or T11(3) MAb alone. Sepharose-linked anti-CD3 MAb did not induce GM-CSF release from NK cells. By S1 analysis, both IL-2 and CD2 stimulation markedly augmented GM-CSF mRNA expression but with very different latencies of onset. IL-2R beta MAb inhibited greater than 85% of GM-CSF release from IL-2-activated NK cells and markedly suppressed IL-2-induced GM-CSF mRNA expression, whereas IL-2R alpha MAb even at 2,000-fold molar excess of IL-2 had little effect (less than 10%) on either GM-CSF release or mRNA expression. Run-on assays showed that GM-CSF is constitutively transcribed in NK cells and that IL-2 and CD2-activated cells had a three- to fourfold increased rate of GM-CSF transcription compared to nonstimulated cells. The t1/2 of GM-CSF mRNA in IL-2-activated NK cells was identical to that of unstimulated NK cells (15 min), whereas GM-CSF mRNA t1/2 in CD2-activated NK cells was increased 2.5-fold. We conclude that GM-CSF production in NK cells is regulated by both the IL-2Rbeta and the CD2 receptor but not by IL-2Ralpha, that both transcriptional and posttranscriptional signals act together to modulate the level of GM-CSF mRNA in NK cells, and that the molecular mechanisms underlying NK cell GM-CSF production are dependent in part on differential surface receptor activation.
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PMID:Production of granulocyte/macrophage-colony-stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 receptor and by the CD2 receptor. 167 38

Acute myeloid leukemia (AML) cells express the surface adhesion proteins intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function associated molecule-3 (LFA-3, CD58). Exposure to the myeloid growth-promoting cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates expression of ICAM-1 and LFA-3 on AML cells but does not increase their sensitivity to lysis by interleukin-2-activated natural killer cells (LAK) in 51Cr assays. However when AML cells are exposed to GM-CSF prior to incubation with LAK, their subsequent clonogenic activity is significantly reduced. If a blocking antibody to ICAM-1 is added during the incubation period of AML with LAK, the inhibitory effect is completely ablated. A less pronounced effect is observed with an antibody to LFA-3. ICAM-1 is expressed on a greater proportion of CD34+ than CD34- AML cells and exposure to GM-CSF induces a significantly greater upregulation of ICAM-1 on leukemic CD34+ cells than their CD34- counterparts. These data suggest that the inhibitory effect of IL-2-activated natural killer cells on clonogenic AML cells is mediated principally via the lymphocyte function associated molecule-1 (LFA-1)/ICAM-1 interaction. Interleukin-2 upregulates LFA-1 expression on natural killer cells. Simultaneous administration of effector cell activators such as IL-2 and target cell modulators such as GM-CSF may have a therapeutic benefit in patients with minimal residual myeloid leukemia.
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PMID:GM-CSF enhances IL-2-activated natural killer cell lysis of clonogenic AML cells by upregulating target cell expression of ICAM-1. 772 3

Interleukin-3 (IL-3) is expressed in T lymphocytes and stimulates the growth of multipotent hematopoietic progenitors. Little is known, however, about the stimuli that lead to IL-3 protein release. We examined IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein secretion in human T lymphocytes following activation via the TCR/CD3 complex, the CD2 receptor, and the IL-2 receptor. GM-CSF mRNA expression and protein release were found in CD3 and CD2 activated T cells with maximum GM-CSF release following stimulation with IL-2. IL-3 protein release is regulated via the CD2 receptor with virtually no IL-3 release after T cell stimulation via CD3. In contrast, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This suggests that upregulation of IL-3 protein release following T cell stimulation via CD-2 occurs largely at the translational or posttranslational level. These data also indicate that differential control of cytokine production can occur in response to activation of the alternative T cell receptor. Interaction of the T cell CD2-receptor with its natural ligand LFA-3 expressed on stromal cells might represent a regulatory mechanism for rapid release of IL-3, facilitating proliferation of multipotent hematopoietic cells.
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PMID:Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation. 860 4

This study was undertaken to investigate the immunomodulatory effect of clarithromycin against synovial fibroblast-like cells (synoviocytes). Synovial tissue obtained from rheumatoid arthritis (RA) or osteoarthritis (OA) patients was enzymatically digested to separate synoviocytes. The synoviocytes were cultured with or without cytokines in the presence of various concentrations of clarithromycin. The expression of costimulatory molecules was examined on the surface of the synoviocytes, using specific MoAbs and flow cytometry. The production of cytokines by synoviocytes was also measured using an immunoenzymatic assay. Finally, autologous T cells were stimulated by interferon-gamma (IFN-gamma)-treated synoviocytes in response to purified protein derivative (PPD). In some experiments, MoAbs specific for costimulatory molecules or clarithromycin were added and 3H-thymidine incorporation was counted. Intercellular adhesion molecule-1 (ICAM-1), LFA-3 and vascular cell adhesion molecule-1 (VCAM-1) were detected on the surface of both RA and OA synoviocytes. However, ICAM-2, B7-1 and B7-2 were not detected, and cytokines failed to induce these molecules. Both spontaneous and up-regulated expression of ICAM-1, LFA-3 and VCAM-1 by IFN-gamma, IL-1beta or 12-o-tetradecanoyl phorbol 13-acetate (TPA) were markedly suppressed by clarithromycin in a dose-dependent manner at concentrations between 0.1 and 10 microg/ml. The production of IL-1beta, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not IL-1alpha and tumour necrosis factor-alpha (TNF-alpha) by synoviocytes was detected. Clarithromycin significantly suppressed the production of these cytokines, but did not enhance IL-10 production. Finally, autologous T cells were stimulated by IFN-gamma-treated synoviocytes in response to PPD. As clarithromycin suppressed HLA-DR and costimulatory molecule expression was enhanced by IFN-gamma, autologous T cell proliferation was markedly inhibited by clarithromycin. Clarithromycin has a considerable immunosuppressive effect on synoviocytes by inhibiting costimulatory molecule expression, cytokine production and antigen-specific T cell proliferation induced by synoviocytes.
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PMID:Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells. 909 36

To determine the effect of growth factor mobilization on the expression of adhesion molecules, we compared CD34+ progenitor cell (PC) populations from steady-state bone marrow (BM) with granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized apheresis products (peripheral blood stem cell (PSC)) using flow cytometry. To increase the accuracy of this analysis, CD34+ cells were enriched (MiniMACS) before cytometric analysis. A significantly lower expression of very late antigen-4 (VLA-4), leukocyte function antigen-1 (LFA-1) and LFA-3 were observed on PSC compared to BM CD34+ cells. In addition, significantly lower mean fluorescence intensity (MFI) of VLA-4, VLA-5, intercellular adhesion molecule-1 (ICAM-1), and sialyl Lewisx were observed on PSC as compared to BM CD34+ cells. Significantly higher levels of L-selectin and CD44 expression were observed on PSC as compared to BM CD34+ cells based on frequency and MFI (P < or = 0.05). In addition, the duration of GM-CSF administration or number of prior aphereses had no effect on adhesion molecule expression. These data suggest that decreased expression of adhesion molecules including VLA-4, LFA-1, ICAM-1 and LFA-3 play a role in PC mobilization. Based on these studies, we suggest that PC mobilization occurs as a stochastic process and is associated with the selection of CD34+ cells with low adhesion molecule expression.
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PMID:GM-CSF-mobilized peripheral blood CD34+ cells differ from steady-state bone marrow CD34+ cells in adhesion molecule expression. 920 10

We have transfected human melanoma cell line 518A2 with the cDNA encoding interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and compared cytokine-producing clones for their ability to induce melanoma-specific cytotoxic T lymphocytes (CTL) from autologous peripheral blood mononuclear cells (PBMC) in vitro. The parental cell line expressed HLA-A1, HLA-A2, ICAM-1, LFA-3, in addition to the common CTL antigens MAGE-1, MAGE-3, tyrosinase, gp100, and Melan-A/MART-1. Stimulation of autologous PBMC responders with the IL-2-transfected clone 518/IL2.14 specifically induced CTL lines reactive with all cell lines derived from the autologous patient. Strikingly, GM-CSF-transfected 518A2 cells did not induce anti-tumor CTL reactivity. CTL induction against 518/IL2.14 was independent of HLA class II expression or CD4 help. The parental cell line 518A2 gained immunogenic properties when high concentrations of IL-2 were supplied exogenously, indicating that IL-2 produced and present at high levels locally by itself enhanced immunogenicity. From the autologous CTL line reactive with 518/IL2.14, clones were generated against an as yet unknown antigen, which was present in all autologous melanoma cell lines as well as in 7 of 15 HLA-A2+ melanoma cell lines tested, but not in melanocytes. These results will be discussed with respect to the possibility of using IL-2-transfected melanoma cells as a vaccine for treatment of patients with melanoma.
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PMID:Transfection of IL-2 augments CTL response to human melanoma cells in vitro: immunological characterization of a melanoma vaccine. 933 41

We developed a human naive T-helper (Th) cell differentiation model with anti-CD3 monoclonal antibody (MoAb), using a B-cell line as source of costimulation. In this system, we examined the contribution of the T-cell receptor (TCR)/CD3-derived signals and that of lymphocyte function-associated antigen-1 (LFA-1) and CD2 in regulating Th-cell subset differentiation. We found that lowering the level of anti-CD3 MoAb decreased tumour necrosis factor-alpha (TNF-alpha) production, while increasing secretion of the Th2 cytokines, interleukin-5 (IL-5) and interleukin-13 (IL-13). Secretion of interferon-gamma (IFN-gamma) was not influenced by the strength of the anti-CD3 signal. Under conditions where Th0 cells are generated, co-culture with anti-CD2 F(ab')2 MoAb led to the generation of Th cells that secreted 30-35% less IL-5, while not affecting secretion of IFN-gamma or granulocyte-macrophage colony-stimulating factor (GM-CSF). By contrast, anti-CD18 MoAb F(ab')2 inhibited IFN-gamma and GM-CSF levels only in the primary stimulation, but did not affect cytokine levels after restimulation. Neither anti-CD2 nor anti-CD18 F(ab')2 MoAbs could alter cytokine secretion profiles of peripheral blood-derived memory/effector Th cells. Our results indicate that acquisition of IL-5 secretion capability by Th cells is regulated mainly by signals transduced by the TCR/CD3 complex and by the presence of interleukin-4 (IL-4), while the CD2/LFA-3 pathway plays an additional, but minor, role. These regulatory CD2-derived signals, however, are distinct from those generated by the TCR/CD3 complex.
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PMID:Acquisition of interleukin-5 secretion by human naive T-helper cells is regulated by distinct signals from both the T-cell receptor/CD3 complex and CD2. 962 27

Carcinoembryonic antigen (CEA) is a glycoprotein that is normally expressed in certain parts of the body and commonly overexpressed in most carcinomas of the colon, rectum, breast, lung, pancreas, and gastrointestinal tract. Increased expression of CEA promotes increased intercellular adhesions, which may lead to metastasis. Carcinoembryonic antigen is often used as a serologic marker of malignancy because of its overexpression in cancer as well as its measurability in serum. However, because CEA is normally expressed in the body, the immune system commonly becomes tolerant to it. If this tolerance can be overcome without leading to autoimmune disease, CEA vaccination therapy could be immensely beneficial to cancer patients. A number of preclinical and clinical studies have been conducted on the use of recombinant CEA-vaccinia virus vaccines and recombinant ALVAC-CEA vaccines. In general, the vaccines have been well tolerated and effective at inducing CEA-specific cytotoxic T-cell responses, especially when used in the presence of the T-cell costimulatory molecule B7.1. "Prime and boost" techniques combining both types of vaccines and the addition of cytokines such as granulocyte-macrophage colony-stimulating factor have resulted in enhanced T-cell responses. The combination of vaccinia or ALVAC vaccines with a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3) has also stimulated significant T-cell increases. This review summarizes these studies and discusses the role of CEA in cancer immunotherapy.
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PMID:Carcinoembryonic antigen-based vaccines. 1288 10