Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00035 (CSF)
 30,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of different recombinant human cytokines and cytokine inhibitors were compared in a culture system in which cell contact with mutant EL-4 thymoma cells of murine origin efficiently stimulates human B cell proliferation and Ig secretion in conjunction with human T cell supernatant. IL-1 alpha, IL-1 beta, TNF-alpha, and IL-2 co-stimulated B cell proliferation and IgM, IgG, and IgA secretion, whereas IL-3, IL-4, IL-5, IL-6, IFN-gamma, or GM-CSF had weak or no activity in this regard. In contrast, TGF-beta 1 was strongly inhibitory. A very strict hierarchy of cytokine interactions was found in that IL-1 was necessary to induce TNF-alpha responsiveness, and TNF-alpha the IL-2 responsiveness, of the B cells. Most likely the small number of starting B cells in the present assay (300 FACS-separated B cells/200 microliters) minimized the effects of autocrine B cell factors. IL-4 together with IL-1 induced IgE secretion, and the IgE secretion was further increased by TNF-alpha. IFN-gamma had no modulatory effect on the IL-4 dependent IgE response in this system. Pretreatment of B cells with IL-1R antagonist (IL-1ra, which binds to IL-1R) or addition of soluble TNF receptor type 1 (sTNF-R55, which binds to TNF) completely inhibited the IL-1 or TNF-alpha effects, respectively. This occurred in a specific manner; the inhibition was reversed by a large excess of cytokine. IL-1ra also inhibited a B cell response induced by PMA-preactivated EL-4 cells alone. Because B cells responding to such preactivated EL-4 cells did not acquire TNF-alpha responsiveness, no IL-1 was apparently involved under this assay condition. It appears, therefore, 1) that IL-1ra can act on B cells and 2) that this antagonist may not only block IL-1R, but may provide a direct or indirect inhibitory signal interfering even with IL-1-independent B cell activation.
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PMID:Effects of eleven cytokines and of IL-1 and tumor necrosis factor inhibitors in a human B cell assay. 131 59

Recent investigations indicate that malignant melanoma cells can produce distinct cytokines. While differences in the production of single cytokines have been observed among different melanoma cell lines, the extent of variability in the production of single and multiple cytokines between individual melanoma cell lines has not been as thoroughly investigated. A heterogeneity in melanoma cell cytokine production could have important implications for the biology of this aggressive neoplasm since certain cytokines may act as autocrine growth factors or be potent modulators of host immune response to the developing tumor. The purpose of this study is to assess the cytokine production profile of two widely available human melanoma cell lines, A375 and G361. The A375 cell line constitutively expressed the mRNA for IL-1 alpha, IL-1 beta and PDGF-A, with increased expression of these cytokines after induction with PMA. GM-CSF mRNA was expressed by the A375 melanoma line only after induction with PMA. No IL-6 mRNA was detected in the A375 melanoma cell line. The cell culture supernatants from the A375 cells likewise contained a parallel increase in IL-1 activity as determined in the D10 bioassay and secreted GM-CSF and PDGF-AA as measured by ELISA. In contrast, the G361 cell line did not express IL-1, GM-CSF or PDGF-A mRNA (constitutively or after PMA induction) but expressed only IL-6 mRNA and secreted IL-6 activity after PMA induction. These results demonstrate a significant heterogeneity in the production of IL-1 alpha, IL-1 beta, IL-6, GM-CSF, and PDGF in two distinct melanoma cell lines. This study demonstrates that individual melanoma cell lines express and secrete multiple cytokines both constitutively and after stimulation with PMA. The immunodulating and mitogenic properties of these melanoma-derived cytokines may have implications in determining the biologic behavior of different malignant melanomas.
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PMID:Heterogeneity of cytokine production by human malignant melanoma cells. 134 59

To investigate the relationship between cytokine production and the increased levels of serum IgE and peripheral eosinophilia commonly accompanying human helminth infections, we studied the ability of PBMC of normal (N1) (n = 18) and eosinophilic individuals with helminth infections (H1) (n = 9) to produce IL-3, IL-4, IL-5, granulocyte-macrophage-CSF, and IFN-gamma in vitro after stimulation with PMA (50 ng/ml) and ionomycin (1 microgram/ml). The two groups differed in both the levels of serum IgE and eosinophilia. For mitogen-induced production of granulocyte-macrophage-CSF and IFN-gamma, there was no difference in cytokine production between the two groups. In marked contrast, supernatants from PBMC of infected individuals had significantly higher levels of IL-4 (mean = 213 pg/ml for N1 and 944 pg/ml for H1, p less than 0.02), IL-5 (mean = 180 pg/ml for N1 and 1118 pg/ml for HL, p less than 0.001), and IL-3 (mean = 13900 pg/ml for N1, 28029 pg/ml for H1, p less than 0.05). In addition, helminth-infected patients had approximately 5-fold greater numbers of T cells capable of producing IL-5 and 2.5-fold greater frequency of IL-4-secreting cells than did normal individuals; GM-CSF- and IFN-gamma-producing T cell numbers were not significantly different in the two groups. IL-3-producing cell frequencies could not be evaluated by this method. There was a direct correlation between IL-4 production and IL-5 production at the level of both protein production and frequency of T cells capable of producing these cytokines. These data indicate that individuals with reactive eosinophilia and elevated serum IgE have an expanded population of lymphocytes producing IL-4 and IL-5 and the association of the two suggests that the regulation of IL-4 and IL-5 may be linked.
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PMID:Parallel regulation of IL-4 and IL-5 in human helminth infections. 135 Feb 92

CD13 has proved to be a useful cell surface marker for depicting haematopoietic cells of the myeloid and monocytic lineages. Sequence data has shown CD13 to bear strong homology to Aminopeptidase-N. Expression of this antigen on myeloid leukaemic cells is, however, variable. We have looked at the effects of a phorbol ester PMA and a haematopoietic growth factor GM-CSF on the expression of CD13 displayed by a selected group of myeloid leukaemias at presentation and by normal peripheral blood granulocytes. We have found that PMA but not GM-CSF was able to stimulate CD13 expression on fresh myeloid leukaemic cells but granulocytes were stimulated by either PMA or GM-CSF. In addition, we have correlated CD13 expression with Aminopeptidase-N enzyme activity on fresh myeloid leukaemic cells. These results suggest that CD13 is functionally active on leukaemic cells and normal granulocytes.
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PMID:Induction of CD13 expression on fresh myeloid leukaemia: correlation of CD13 expression with aminopeptidase-N activity. 135 31

Fc receptors (FcR) are of importance in immune and inflammatory reactions. FcR expression as mRNA and surface protein was therefore examined in the myelomonocytic cell line, U937, after stimulation with phorbol ester (PMA), in the presence of seven different cytokines (interferon-gamma [IFN gamma], IFN alpha, granulocyte-macrophage colony-stimulating factor [GM-CSF], tumour necrosis factor-alpha [TNF alpha], TNF beta, interleukin-beta [IL-1 beta], IL-2) or dexamethasone. HLA class I and CD11b expression were also examined. Cell surface expression of FcRI and II was measured by flow cytometry using monoclonal antibodies, and the mRNA of FcRII was measured with cDNA or oligonucleotide probes. The major findings were: PMA increased cell surface FcRI, FcRII and CD11b, but decreased HLA; PMA caused a fivefold increase in all three FcRII RNA transcripts (2.5, 1.5 and 0.9 kb) in Northern analysis; IFN gamma, IFN alpha and GM-CSF increased the expression of FcRI and II, and there was no effect with IL-1 beta, IL-2, TNF alpha or TNF beta (only GM-CSF increased the expression of CD11b); all cytokines further increased FcRI and FcRII expression in the presence of PMA; HLA expression was also increased in the presence of PMA, IFN alpha and IFN gamma; dexamethasone reduced the levels of FcRI and II in cells stimulated with PMA with or without cytokines. Thus stimulatory agents and cytokines can alter the expression of surface Fc gamma R and mRNA encoding FcRI or II, providing potential control mechanisms for the modulation of these receptors in inflammatory responses.
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PMID:Effects of PMA, cytokines and dexamethasone on the expression of cell surface Fc receptors and mRNA in U937 cells. 135 19

Human alloreactive T lymphocyte clones derived from cells invading a rejected kidney allograft, were analyzed for their ability to transcribe eleven cytokine genes under phorbol ester (PMA) plus calcium ionophore (CaI A 23187) stimulation. In addition to the positive signal previously obtained for IL-2 transcripts, strong specific patterns were seen with cytoplasmic dot hybridizations for IFN gamma and GM-CSF mRNAs in all the 17 clones screened. For the remaining transcripts (IL-3, IL-4, IL-5, IL-6, TNF alpha, LT, M-CSF and HILDA/LIF), these techniques proved to be inadequate. Northern-blots were therefore performed on three clones exhibiting different phenotypes (CD4+ CD8- non cytotoxic, CD4+ CD8- cytotoxic and CD4- CD8+ cytotoxic). Positive specific signal with the eleven probes could be obtained. Nevertheless, the IL-6 message was found only in the helper clone and the TNF alpha transcript appeared at a later time point compared to the other cytokine messages (its maximum expression was observed around 24 hours post-stimulation). In conclusion, we demonstrate that under PMA+CaI activation, one clone is able to simultaneously transcribe at least eleven lymphokine genes. Except, perhaps for IL-6, the pattern of lymphokine transcription did not permit us to distinguish between different lymphocyte subsets.
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PMID:Simultaneous transcription of eleven cytokines in human alloreactive T lymphocyte clones after stimulation by phorbol ester and A23187. 136 87

The CD20 molecule is a unique phosphoprotein exclusively expressed on B cells during most stages of B cell ontogeny. We here report that rIL-4 down-regulates the expression of CD20 with anti-Leu-16 mAb (clone L27) on both unstimulated and anti-mu preactivated normal and leukemic B cells. None of the other recombinant lymphokines tested (IL-1, IL-2, IL-3, IL-6, IFN-alpha, and IFN-gamma, granulocyte/macrophage-CSF, transforming growth factor-beta, TNF-alpha, and lymphotoxin) decreased CD20 expression. Incubation of unstimulated or anti-mu preactivated B cells with IL-4 did not affect the steady state CD20 mRNA, suggesting that IL-4 exerted its effect mainly at a nontranscriptional level. Hence, IL-4 selectively down-regulates the CD20 epitope recognized by clone L27 without affecting seven other different epitopes, indicating that IL-4 acts by modifying the conformation of the CD20 molecule rather than by inhibiting its production or inducing its internalization. IL-4 most likely utilizes a protein kinase C-independent signal transduction pathway to modify CD20 molecule inasmuch as staurosporine, an inhibitor of protein kinase C, antagonizes phorbol esters (PMA) but not IL-4-induced CD20 down-regulation. In contrast, anti-CD40 mAb reverses the IL-4 but not the PMA inhibitory effect on CD20 expression. Given that CD20 may be part of a Ca2+ ion channel and plays a role in B cell activation and proliferation, it is proposed that the ability of anti-CD40 mAb to maintain the CD20 molecule in a given epitopic configuration on IL-4-stimulated B cells may be related to the long term proliferation of normal B cells that are strictly dependent on the presence of IL-4 and cross-linked anti-CD40 mAb for their continuous growth.
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PMID:IL-4 induces conformational change of CD20 antigen via a protein kinase C-independent pathway. Antagonistic effect of anti-CD40 monoclonal antibody. 137 68

Pretreatment with recombinant human granulocyte CSF (G-CSF) protected mice in two different models of septic shock. Intravenous injection of 250 micrograms/kg G-CSF to mice prevented lethality induced by 5 mg/kg LPS. Injection of 50 micrograms/kg G-CSF protected galactosamine-sensitized mice against LPS-induced hepatitis. In either case, this protection was accompanied by a suppression of LPS-induced serum TNF activity. In contrast, when galactosamine-sensitized mice were pretreated with 50 micrograms/kg murine recombinant granulocyte/macrophage CSF instead of G-CSF and subsequently challenged with LPS, serum TNF activity was significantly enhanced and mortality was increased. The suppressive effect of G-CSF on LPS-induced TNF production was also demonstrated in rats. In vivo, no TNF was detectable in the blood of LPS-treated rats, which had been pretreated with G-CSF. Ex vivo, alveolar macrophages, bone marrow macrophages, Kupffer cells, or peritoneal macrophages prepared from G-CSF-treated rats produced significantly less TNF upon stimulation with LPS than corresponding populations from control rats. However, when these macrophage populations were incubated with G-CSF in vitro, LPS-induced TNF production was unaffected. These data suggest that the G-CSF-mediated suppression of TNF production is not a direct effect of G-CSF on macrophages. To examine whether, independent of the protection against LPS, G-CSF treatment still activated neutrophils, it was demonstrated that granulocytes from G-CSF-treated rats were primed for PMA-induced oxidative burst and for ionophore/arachidonic acid-stimulated lipoxygenase product formation. The experiments of this study support the notion that G-CSF is a negative feedback signal for macrophage-derived TNF-alpha production during Gram-negative sepsis.
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PMID:Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-alpha. 137 68

We studied the effect of hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte [G]-CSF, interleukin (IL)-1, IL-3, IL-5, IL-6, and macrophage [M]-CSF) on differentiation and functional activity of human eosinophilic HL-60 cells (Eos-HL-60) and compared them with effects on parental HL-60 promyelocytic leukemia cells. Purified biosynthetic GM-CSF and IL-5 enhanced cell proliferation and induced eosinophilic differentiation in the eosinophilic subline in both liquid and agar cultures. IL-3 and IL-6 stimulated cell proliferation but had no effect on cell differentiation, whereas IL-1 and G-CSF affected neither differentiation nor proliferation of Eos-HL-60 cells under the conditions tested. GM-CSF-, IL-3-, and IL-5-treated Eos-HL-60 cells showed increased O2- production in response to phorbol esters (PMA), enhanced phagocytosis of Candida albicans, and release of the enzymes arylsulfatase, beta-glucuronidase and eosinophil peroxidase (EPO). The degranulation of eosinophils induced by GM-CSF, IL-5, and IL-3 may have relevance to the potential clinical toxicity of these hematopoietins, which also stimulate eosinophilopoiesis. G-CSF had no effect on enzyme release, oxidative metabolism, or phagocytic capacity of Eos-HL-60 cells. IL-5 did not affect proliferation, differentiation, or enzyme release in promyelocytic HL-60 cells. These results indicate the specificity of IL-5 for the eosinophil lineage, confirm the effects of GM-CSF and IL-3 on eosinophilopoiesis and mature eosinophil function in a model system, and indicate the absence of G-CSF and IL-1 stimulation of eosinophils. The Eos-HL-60 line is a useful model for studying human eosinophil responses to cytokines.
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PMID:Differentiation and functional activity of human eosinophilic cells from an eosinophil HL-60 subline: response to recombinant hematopoietic growth factors. 137 88

The effect of platelet factor 4 (PF4) on the growth of human erythroleukemia cell line (HEL) and the binding characteristics of iodine 125-labeled PF4 to cells were studied to determine the mechanism of action of PF4. HEL cells were cocultured with various doses of PF4 in either a plasma clot system for colony assay or a liquid system for tritiated thymidine incorporation. A significant inhibition of HEL colony growth and tritiated thymidine incorporation was seen at PF4 doses of 1 microgram/ml and 0.5 microgram/ml, respectively. The inhibitory effect of PF4 could be abrogated by the addition of heparin (5 to 10 micrograms/ml). Enzyme-linked immunosorbent assay showed that PF4 had no obvious effect on the expression of platelet glycoprotein IIb/IIIa of HEL cells. Binding of 125I-PF4 to HEL cells reached equilibrium within 20 to 30 minutes with dissociation constant of 1.3 x 10(-10)M and Bmax of 6.3 pmol/10(5) cells and was inhibited by an excess of unlabeled PF4, beta TG, and heparin but was not affected by PMA, IL-3, IL-6, GM-CSF, and interferon-alpha. PF4 did not affect the binding of 125I-IL-3 and 125I-IL-6 to HEL cells. These data demonstrate that PF4 inhibits the growth of HEL cells by specific binding to HEL cells and suggest that the action of PF4 may be associated with the heparin-binding sites of the molecule.
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PMID:Inhibitory effect of platelet factor 4 (PF4) on the growth of human erythroleukemia cells: proposed mechanism of action of PF4. 140 41


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