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U937-derived fibroblast-activating factor
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(ATCC: CRL 1593) A human cell line established from a diffuse histiocytic lymphoma of a 37 year old male patient. This cell line is one of the few cell lines displaying many monocytic characteristics and has thus served as a model for the differentiation of monocytes and macrophages in vitro.
The cells are committed to the macrophage branch of the myeloid lineage and can be induced by a variety of agents to mature from a promonocytic into a monocytic stage of development. This process is accompanied by the acquisition of a number of morphological and functional attributes normally associated with mature macrophages and requires the expression of the fes oncogene.
The cell line constitutively produces IL1 and also produces GM-CSF, ECEF (eosinophil cytotoxicity-enhancing factor), VPF (vascular permeability factor), and LBIF (lymphocyte blastogenesis inhibitory factor). Lehmann et al (1998) have shown that GM-CSF induces the production of IL10 in U937 cells. GM-CSF and TNF-alpha have additive effects on IL10 production but act independent of each other. Jenkins et al (1997) have demonstrated that the expression of one of the molecular forms of IL1ra, icIL1ra, mRNA in U937 cells is inducible by treatment with phorbol 12-myristate 13-acetate. Ohguchi et al (1998) have reported that Activin A enhances the production of IL1ra in activated U937 cells. Berger et al (1993) have reported that GM-CSF and IL4 are inducers of IL1ra in U937 cells differentiated by phorbol esters. IL1-alpha, IL1-beta, and TGF-beta are weak inducers and IL2, PDGF, aFGF, bFGF, EGF, G-CSF, IL3, IL5, IL6, IFN-gamma, TNF-alpha and IL1ra itself have no effect.
The cells also secrete into the conditioned medium an uncharacterized factor (see: THP-1-derived growth-promoting activity) that promotes the growth of a large variety of cell types. They also secrete a Monocyte-derived scattering factor. The cells have been shown to secrete ECI [endothelial cell inhibitor]. Conditioned medium also contains EMAP-2 (Tas et al, 1997).
Cell activation of U937 can be elicited by treatment with conditioned medium of lymphocytes. They display a pronounced antibody-dependent cell-mediated cytotoxicity (see: ADCC) against a number of erythroid and neoplastic target cells.
As shown by Defacque et al (1999), Vitamin D and retinoids cooperate to inhibit the proliferation and induce differentiation of U937 cells by a mechanism iinvolving the production of TGF-beta.
Zella et al (1998) have shown that IFN-gamma increases the expression of chemokine receptors CCR1, CCR3, and CCR5 in U937 cells.
Phorbol esters, retinoic acid, 1-25 dihydroxyvitamin D3, IL6 (see: DIF, differentiation inducing factor), IFN-gamma, and TNF-alpha induce the differentiation of U937 cells into cells resembling monocytes and macrophages secreting M-CSF. IFN-gamma also upregulates the expression of TRAIL, and the cells express the receptor DcR-2 (Phillips et al, 1999).
Guerrero et al (2000) have shown that melatonin enhances IL6 production by U937 cells if the cells are activated by treatment with IFN-gamma, which induces the production of nuclear receptors for melatonin. Resting cells, which only express membrane receptors do not respond.
Suk and Cha (1999) have shown that thrombin is a strong inducer of IL8 expression in U937 cells. IFN-gamma enhances thrombin induced IL8 production and prostaglandin E2 acts as a negative regulator.
TNF-alpha and IFN-gamma increase the amount of cellular mRNA for H-Ferritin, but not L-Ferritin. IL1-beta has no effect (Fahmy Young, 1993).
GM-CSF inhibits the colony growth of U937 cells in agar culture and induces cell death by apoptosis (Okuma et al, 2000). This effect is, at least in part, due to the induction of secretion of TNF-alpha. Proliferation of U937 cells has been shown to be inhibited by VEGI (Haridas et al, 1999).
Incubation of U937 cells GM-CSF makes them responsive to induction of TNF by bacterial lipopolysaccharides. Treatment with IL6 inhibits TNF production. In the presence of GM-CSF differentiation is induced by Oncostatin M. U937 cells have been shown to express surface FAS antigen but the agonistic anti-FAS monoclonal antibody 7C11 does not induce cell death by apoptosis in these cells (Kim et al, 2000).
Mori et al (2000) have shown that viral IL6 encoded by human herpesvirus HHV-8 increases production of IL6 by U937 cells. Biswas et al (1998) have shown that IL6 is a strong inducer of the secretion of MCP-1 by U937 cells and that is has no effect on the production of other chemokines, including RANTES, MIP-1-alpha, MIP-1-beta, and IL8.
A marked suppression of clonogenicity is observed using combinations of LIF and G-CSF. U937 cells respond by diminished spontaneous migration (see also: Motogenic cytokines) when confronted with affinity-purified soluble fragments of CD23.
The cytotoxic activity of TNF-alpha for U937 cells is markedly reduced by pretreatment with ADF (adult T-cell leukemia-derived factor) and enhanced by low concentrations of IL6. The growth of U937 cell is inhibited by TGF-beta at doses ranging from 0.025 to 2.5 ng/mL. It is inhibited also by a differentiation factor for monocytes of 45-55 kDa, distinct from IFN-gamma, TNF-alpha, or GM-CSF, produced by CD4(+) CD8(+) T-cells after cell activation.
Variants of U937 cells capable of long-term growth in serum-free medium have been described also. Monoclonal antibodies to the eosinophil cytotoxicity-enhancing factor (see: ECEF) have been used to select U937 variants that differentiate in response to suboptimal doses of PMA (see also: Phorbol esters).
Cell extracts from U937 cells have been shown to contain catalase which is identical with Erythrocyte-derived growth-promoting factor. Treatment of the cell extracts with an irreversible catalase inhibitor, aminotriazole, abolishes both the catalase and growth-promoting activities.
Kaszubowska et al (2001) have described U937G and U937M, two sublines of U937 cells that may be useful to study TNF actions. U937G cells are resistant to the cytotoxic action of TNF in the absence of cycloheximide. U937M cells are sensitive to the cytotoxic action of TNF in the presence and absence of cycloheximide.
For an overview of other cell lines used in research on cytokines see: Cell lines in Cytokine Research. For other related/relevant entries see also: Cell types.
Copyright © 2012 by H IBELGAUFTS. All rights reserved.
ENTRY LAST MODIFIED: January 2002
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