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)

The beta 2 integrins are composed of a common 95-kD beta-subunit (CD18) and one of three possible alpha-subunits: CD11a, CD11b, or CD11c. These molecules are involved in neutrophil adhesion, diapodesis, chemotaxis and phagocytosis. In this study, the effects of traumatic injury on neutrophil expression of these alpha-subunits were investigated. Neutrophils from patients with severe trauma (n = 30) were stained with fluorescent anti-CD11a, -CD11b, or -CD11c. The percentage of positive neutrophils and the mean channel fluorescence were assayed by flow cytometry. In 10 patients and 10 normals, the effects of granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on alpha-subunit expression were evaluated. Ninety-four +/- 2% (s.e.m.) of normal neutrophils were CD11a+, 89 +/- 1% were CD11b+ and 89 +/- 8% were CD11c+. Only 65 +/- 2% of patient neutrophils were CD11a+, 45 +/- 5% were CD11b+ and 8 +/- 1% were CD11c+. Culture of normal neutrophils without colony-stimulating factors resulted in reduced expression of CD11a and CD11c, but up-regulation of CD11b. Down-regulation of CD11a and CD11c was partially reversed by colony-stimulating factors (30 U/ml). CD11b receptor density was further up-regulated by GM-CSF and G-CSF. Treatment of patient neutrophils with colony-stimulating factors in culture resulted in up-regulation of alpha-subunits as well. GM-CSF appeared to have the greater effect. These results indicate that colony-stimulating factors may have a clinical role in improving beta 2 integrin expression, and suggest a use in these infection-prone patients.
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PMID:Reduced PMN beta 2 integrins after trauma: a possible role for colony-stimulating factors. 768 73

Interleukin-2 (IL-2)-dependent large granular lymphocytes (LGL) with a distinctive surface phenotype were generated from histologically normal duodenal biopsy tissues. Immunoperoxidase staining of the mucosa with an anti-CD56 monoclonal antibody revealed LGL localized in the lamina propria rather than in the epithelium. Light and electron microscopy demonstrated azurophilic and electron-dense cytoplasmic granules. Flow cytometry analysis revealed that these cells express CD45, CD56, CD2, CD7, CD11a, CD18, CD69 and the intermediate affinity (p70) IL-2 receptor (IL-2R) but not CD57, CD16, CD3, CD4, CD5, CD8, CD45RA, CD25, or the high affinity p55 IL-2R. The LGL proliferated when cultured in the presence of human rIL-2 but not in the presence of human rIL-4. Functional studies demonstrated that the LGL had strong cytotoxicity against natural killer (NK) target cells, K562, but not NK-resistant targets such as Colo 205, Melanoma and Epstein-Barr virus (EBV)-transformed B-cell lines. The LGL expressed genes for IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha) and the corresponding cytokines were detected in culture supernatant. These results provide evidence for an important role of gut mucosal LGL in the induction and regulation of inflammation and immunity in the gut.
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PMID:Morphological, phenotypic and functional characteristics of a pure population of CD56+ CD16- CD3- large granular lymphocytes generated from human duodenal mucosa. 769 28

Interleukin-13 (IL-13) is a pleiotropic cytokine that inhibits the production of inflammatory cytokines of monocytes. We investigated the effects of IL-13 on the clonal growth of human hematopoietic progenitors. IL-13 alone did not support any colony formation. IL-13 markedly suppressed macrophage colonies that were formed in the presence of IL-3 and erythropoietin, granulocyte-macrophage colony-stimulating factor, or macrophage colony-stimulating factor. Macrophage colony cells showed dendritic cell-line morphology and cellular aggregates. IL-13 did not affect granulocyte colony and erythroid burst formation. Delayed addition of IL-13 and replating onto the culture dishes with IL-13 showed that macrophage colony formation was suppressed during days 8 and 14 of culture. These results indicate that IL-13 affects the growth of the late stage of committed macrophage progenitors. Single-cell culture of isolated CD34+CD33+ cells with IL-13 confirmed that macrophage colony formation was significantly suppressed. These results show that IL-13 directly suppresses the proliferation of differentiating macrophages. In addition, these suppressive effects of IL-13 were synergistic with IL-4. Furthermore, in the liquid culture of bone marrow cells in the presence of IL-13, the number of CD14 (monocyte-macrophage antigen)-positive cells decreased and CD18 (LFA-1 beta)-positive cells increased. It is concluded that IL-13 affects the growth of the late stage of macrophage precursors as well as mature monocytes. Induction of differentiation of human monocytes may be correlated with the suppression of their progenitors.
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PMID:Interleukin-13 selectively suppresses the growth of human macrophage progenitors at the late stage. 778 Jan 35

Leukotriene (LT) and lipoxin (LX) levels were monitored in ionophore-stimulated coincubations of polymorphonuclear neutrophils (PMN) and microvascular kidney glomerular endothelial cells (GEN) to determine the profile of lipoxygenase (LO) products generated during cell-cell interactions and the relative contributions of transcellular pathways to LO product biosynthesis in this setting. LTB4 and LTC4 were the major products formed, as determined by reverse-phase high-performance liquid chromatography and radioimmunoassay. LTB4 and LTC4 levels were increased by 23 and 185%, respectively, in coincubations of PMN and GEN, compared with incubations of PMN alone. In contrast, LXA4 and LXB4 levels were not changed in the presence of GEN. These data suggested that GEN utilize PMN-derived LTA4 to generate LT. In keeping with this hypothesis, LT biosynthesis was enhanced if PMN were primed with human granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that augments LTA4 biosynthesis by activated PMN. The influence of LT on PMN adhesion to GEN was also assessed, since adhesion appears to be a pivotal event in recruitment of PMN in acute glomerulonephritis. Under basal conditions, LTB4 provoked low levels of adhesion via a PMN-directed CD11/CD18-dependent mechanism. The level of adhesion was markedly enhanced by prior priming of PMN with GM-CSF or activation of GEN with tumor necrosis factor-alpha (TNF). LTB4 was as potent in this regard as the complement component C5a, platelet-activating factor (PAF), and interleukin-8 (IL-8), other mediators that contribute to the entrapment of PMN in inflamed glomeruli. LTC4 also provoked PMN-GEN adhesion via a CD11/CD18-dependent mechanism, but, in contrast to LTB4, via actions with GEN. This action of LTC4 appeared to be mediated, at least in part, by induction of PAF synthesis by GEN. Interestingly, LT-induced PMN-GEN adhesion was markedly attenuated following remodeling of PMN phospholipids with 15(S)-hydroxyeicosatetraenoic acid, a product of 15-LO, which has been implicated as an anti-inflammatory eicosanoid in some experimental and human inflammatory diseases. Taken together, these results provide further evidence that 1) transcellular biosynthetic pathways may amplify the profiles of inflammatory mediators and thereby contribute to leukocyte recruitment in acute glomerulonephritis and 2) that products of the 5-LO and 15-LO pathways may exert opposing actions on PMN trafficking during glomerular inflammation in vivo.
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PMID:Lipoxygenase product formation and cell adhesion during neutrophil-glomerular endothelial cell interaction. 784 Feb 35

Complement biosynthesis in monocytes is stimulated by different pathogens and modulated by a variety of cytokines, but little is known about the possible effect of transforming growth factor beta (TGF-beta) on this monocyte function. We therefore studied the effect of TGF-beta 1 and TGF-beta 2 on constitutive, lipopolysaccharide (LPS)- and Candida albicans-induced monocyte biosynthesis of complement components C3 and factor B. Under all three conditions, both forms of TGF-beta (20 ng/ml) induced a two- to fourfold increase in C3 concentration in monocyte supernatants harvested after 2 or 5 days of cell culture, an effect that was abrogated by cycloheximide. In contrast, constitutive and pathogen-induced production of factor B was suppressed by TGF-beta. The effects of TGF-beta on complement production were neutralized by a monoclonal anti-TGF-beta antibody. Moreover, TGF-beta suppressed the pathogen-induced release of granulocyte-macrophage colony-stimulating factor and down-regulated the expression of complement receptor 3 (CD11b/CD18), while the expression of CD11a/CD18, a related beta 2 integrin, was unaffected. These novel effects of TGF-beta emphasize the immunomodulatory significance of this cytokine.
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PMID:Transforming growth factor beta modulates C3 and factor B biosynthesis and complement receptor 3 expression in cultured human monocytes. 785 44

Eosinophils interact with extracellular matrix proteins and endothelial cells through adhesion proteins belonging to the beta 1 and beta 2 subfamilies of integrins. Extending previous observations, we found that tumour necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor stimulated generation of superoxide anion by eosinophils plated on fibronectin-coated surfaces. As studies with adherent neutrophils indicated that TNF might act as activating leucocyte integrins to deliver signals involved in activation of cell functions, we investigated the effects of monoclonal antibodies (mAb) directed against VLA-4 (CD49d/CD29), LFA-1 (CD11a/CD18), CR3 (CD11b/CD18) or the common beta 2 subunit (CD18) on generation of eosinophil toxic oxygen molecules and spreading. We show that cross-linking of members of both the beta 1 and the beta 2 integrin subfamilies triggers eosinophil respiratory burst and spreading. Evidence for the selectivity of anti-integrin mAb effects is derived from the findings that isotype-matched mAb of other specificities (anti-class I MHC Ag, anti-beta 2-microglobulin, anti-CD4) did not trigger eosinophil functions. The findings presented in this paper suggest that integrin-dependent, eosinophil adhesion in sites of allergic reaction may be accompanied by release of toxic oxygen molecules involved in tissue damage.
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PMID:Ligation of members of the beta 1 or the beta 2 subfamilies of integrins by antibodies triggers eosinophil respiratory burst and spreading. 790 78

Secretion of unique eosinophil granule constituents may play a role in allergic and parasitic reactions. Therefore we have investigated possible mechanisms for regulation of secretion in eosinophils. A hemolytic plaque assay and an enzyme-linked immunospot (ELISPOT) assay were developed for detection of secreted eosinophil cationic protein (ECP) from single adherent eosinophils. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced release of ECP in a dose-dependent fashion but 4-alpha-PMA, an analogue that does not activate protein kinase C, did not cause degranulation. Staurosporine and K252a, inhibitors of protein kinase C, decreased PMA-induced ECP secretion. Low concentrations of cytochalasin B enhanced PMA-induced secretion but high concentrations had an inhibitory effect. The calcium ionophores A23187 and ionomycin were weaker secretagogues than PMA. Tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-5, N-formylmethionyl-leucyl-phenylalanine, and lipopolysaccharide caused little or no degranulation in adherent eosinophils. Preincubation of eosinophils with antibodies to CD18, the common beta chain of leukocyte adhesion proteins, resulted in inhibition of PMA-induced ECP release from adherent cells. 1,2-Bis(O-aminophenyl)-ethane-ethane-N,N,N',N'-tetraacetic acid (BAPTA), an agent that acts intracellularly by chelation of calcium, also inhibited PMA-mediated ECP release. In conclusion, PMA induces release of ECP from single adherent eosinophils and the effect appears to be mediated via protein kinase C and, in contrast to that in neutrophils, to be dependent on CD11/CD18 leukocyte integrins.
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PMID:Phorbol ester-induced degranulation in adherent human eosinophil granulocytes is dependent on CD11/CD18 leukocyte integrins. 809 65

Staphylococcal enterotoxin superantigens (SAg) bind class II major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC) and upon cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. In addition, SAg can also deliver negative signals to Ag-specific T cells resulting in a state of unresponsiveness or a loss of viability. The present study examines the functional consequences of a direct interaction of SAg with alloAg-specific class II MHC+ CD4+ T cell lines (TCL). Our results demonstrate that SAg induce programmed death (apoptosis) in a majority of Ag-specific CD4+ T cells accompanied by genomic DNA fragmentation. SAg binding to Ag-specific TCL resulted in a rapid mobilization of intracellular free calcium ([Ca2+]i) and transcription of a number of cytokine genes including interleukin-2(IL-2), IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granzyme B indicating the activation of primed T cells. Both SAg-induced cytokine gene expression as well as subsequent death were significantly inhibited by a tyrosine kinase inhibitor herbimycin A and also by cyclosporin A. SAg-induced death of primed T cells was also inhibited by monoclonal antibodies (mAb) directed at the CD11a/CD18 molecule but not those reactive with other T cell surface molecules such as CD2, CD7, CD28, CD29 or CD49d. None of these mAb, including anti-CD11a/CD18, had any effect on SAg-induced expression of IL-2 and IL-4 genes or SAg-induced [Ca2+]i response. Addition of cytokines such as IL-1 alpha, IL-2, IL-4, IL-6, GM-CSF, IFN-gamma, tumor necrosis factor (TNF-alpha, or TNF-beta), or neutralizing Ab to these cytokines had no effect on SAg-induced death of Ag-specific TCL. The T cells which survived the death-inducing effects of SAg showed down-regulation of the CD3/T cell receptor and up-regulation of CD2 and HLA-DR expression, and upon re-exposure to the same SAg upregulated expression of mRNA for IL-2 and IFN-gamma. Presentation of SAg by B7+ ICAM-1+ LFA-3+ DR+ professional APC was also able to induce the death of Ag-specific TCL. Together these results suggest that the activation with SAg causes programmed death of Ag-specific TCL cells via a mechanism that requires late participation of the CD11a/CD18 molecule.
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PMID:Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism. 810 Jul 73

The role of the leukocyte function-associated antigen-1 (LFA-1) family of integrins (beta 2 integrins) in the interferon-alpha (IFN-alpha) response was examined, using human peripheral blood mononuclear cells (PBMCs) stimulated in vitro by glutaraldehyde-fixed Herpes simplex virus-infected WISH amnion cells. Monoclonal antibodies (mAbs) to the beta 2 chain (CD18) and to the alpha chain of LFA-1 (CD11a) reduced the number of IFN-alpha-producing cells (IPCs) by 30-50%, but mAbs to CD11b or c caused no inhibition. The IB4 mAb to CD18 was inhibitory when added during the first 2 h of the IFN-alpha response, but did not alter its kinetic. In contrast, the IB4 prevented the early enhancement of the IFN-alpha response caused by addition of interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF). However, a delayed down-regulation of the IPC response occurred in such PBMC cultures, and a paradoxical increase in the total production of IFN-alpha. The results suggest that LFA-1 (CD11a/CD18) participates in the early phase of the IFN-alpha response and may be activated by cytokines such as IL-3 and GM-CSF.
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PMID:The leukocyte function-associated antigen-1 (LFA-1) is involved in the interferon-alpha response induced by herpes simplex virus in blood leukocytes. 810 35

Macrophage-like synoviocytes originate in the bone marrow, like other mononuclear phagocytes, and are constantly replaced via the circulation. In rheumatoid synovium sections, 80-100% of the synovial lining cells are macrophage-like cells functioning as antigen processing- and antigen-presenting cells to T lymphocytes. Monocyte and lymphocyte traffic into the rheumatoid arthritis (RA) synovium is mediated by adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules-1 and -2 (ICAM-1 and ICAM-2), as well as monocyte chemotactic protein 1 (MCP-1) and beta 2 integrins (CD11 a,b,c/CD18). Macrophage-like cells in the RA synovium are highly activated based on their morphology, surface class II HLA antigen expression, and synthesis of cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF, and transforming growth-factor beta (TGF-beta). Evidence for type 1 (higher affinity) and type 2 (lower affinity) androgen (ARs) and estrogen receptors (ERs) on macrophage-like synoviocytes in either male or female synovial samples from both RA patients and controls has been reported. In particular, ERs have also been found on CD8+CD29+ CD45R0+ T lymphocytes (memory), infiltrating rheumatoid synovial tissues. Sex hormones have been found to influence macrophage activity in experimental and clinical conditions such as RA. Generally estrogens have immunostimulatory effects, whereas androgens are immuno-suppressive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Macrophages, synovial tissue and rheumatoid arthritis. 839 94


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