Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deregulation of IL-6 production is one of the major causes for human multiple myeloma. Exogenous IL-6 stimulated the proliferation of fresh human myeloma cells and the myeloma cell line, U266, which produced IL-6 spontaneously. Anti-IL-6 antibody and IL-6 antisense oligonucleotide suppressed the IL-6 stimulated myeloma cell proliferation, indicating that IL-6 induced the myeloma cell proliferation via an autocrine loop. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, inhibited the U266 cell proliferation at a concentration of less than 1 ng/ml. At this concentration, okadaic acid suppressed the IL-6-induced IL-6 gene expression of myeloma cells. It seems that the okadaic acid blocked the myeloma cell proliferation by reducing IL-6 synthesis in myeloma cells. In addition, IL-6 itself also regulated IL-6 receptor expression. Analysis by FACScan and RT-PCR showed that anti-IL-6 antibody treatment up-regulated IL-6 receptor expression. Interestingly, the presence of okadaic acid induced the up-regulation of IL-6 receptor expression as well as the down-regulation of IL-6-induced gp130 phosphorylation in the myeloma cells. Taken together, these data suggest that protein phosphatase 1 and 2A are involved in IL-6-mediated autocrine growth of human myeloma cells by modulating IL-6 signaling and IL-6 receptor expression in myeloma cells.
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PMID:Roles of protein phosphatase 1 and 2A in an IL-6-mediated autocrine growth loop of human myeloma cells. 864 Aug 63

We investigated the possible influence of recombinant (r) sIL-6R on the growth of three IL-6 non-responsive or weakly IL-6 responsive long-term myeloma cell lines. The three cell lines chosen for the study (U266, L363 and Fravel) all expressed gp130 but differed in their expression of IL-6R and IL-6. mRNA analysis by northern blot and reverse transcriptase polymerase reaction showed that the cell line U266 was the only one that expressed IL-6 mRNA. Only U266 and L363 expressed IL-6R mRNA. 125I-rIL-6 binding studies and FACS analysis, using biotinylated IL-6 and antibodies directed against the IL-6R and gp130, showed corresponding results on the protein level. Addition of rsIL-6R resulted in induction of IL-6 responsiveness in L363 cells, whereas the 3H-thymidine incorporation of the cell lines U266 and Fravel was unaffected by rsIL-6R addition. In conclusion, the IL-6 unresponsive growth of several long-term myeloma cell lines in vitro can in some, but not all cases, be due to a deficiency in exogenous sIL-6R.
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PMID:Differential interleukin-6 (IL-6) responses of three established myeloma cell lines in the presence of soluble human IL-6 receptors. 864 40

The chemotaxis of human malignant plasma cells is promoted by two extracellular matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds, OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the expression of beta 1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1 cells showed chemotaxis promoted by FN (ChFN) and LN (ChLN). ARH-77 cells showed ChFN but not ChLN. RPMI-8226 cells did not show either ChFN or ChLN. The supernatant from KM-101 cells inhibited the chemotaxis of each of these cell lines regardless of whether the chemotaxis was promoted by FN or LN. Among the cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6 receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6) also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is probably transduced via the signal transducing receptor component, gp130. The chemotaxis-regulatory effect is another previously unrecognized function of this pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow microenvironment of patients with multiple myeloma appears to be favourable for the localization of myeloma cells there.
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PMID:Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines. 865 70

A consensus regarding myeloma cell growth factor responsiveness and ability to produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from patients with aggressive disease. Extensive characterization of these cell lines revealed considerable heterogeneity at several levels. Growth factor responsiveness was initially addressed. Although the potent myeloma cell growth factor, IL-6, induced the proliferation and allowed for the expansion of all three cell lines, a panel of other cytokines elicited heterogeneous responses in each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor necrosis factor-alpha also stimulated DNA synthesis in all three cell lines; however, the magnitude of the response was generally lower than that observed in cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6 cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells. The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP-6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR analysis demonstrated that all three cell lines expressed IL-6 mRNA. However, when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6 bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically active IL-6. In summary, although all three of these cell lines were established from myeloma patients, the heterogeneity observed between these cell lines was considerable and may reflect, as well as provide tools to study, the heterogeneity observed in clinical disease.
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PMID:Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6. 865 85

We obtained a human myeloma cell line (XG4-CNTF) whose growth was completely dependent on addition of ciliary neurotrophic factor (CNTF). Half-maximal proliferation was induced by adding 20 pg/mL CNTF. Response to CNTF correlated with expression of membrane CNTF receptor alpha-chain (CNTFR alpha), as shown by PCR analysis and immunostaining with anti-CNTFR alpha antibodies. CNTF-induced proliferation was completely inhibited by antibodies to gp130 interleukin-6 (IL-6) transducer, unlike antibodies to IL-6 or IL-6 receptor (IL-6R). Growth of XG4-CNTF cells using the gp130 IL-6 transducer was also supported by other cytokines: IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OM). This cell line should be very useful for studying the interactions of IL-6-related cytokines with their receptors.
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PMID:A ciliary neurotrophic factor-sensitive human myeloma cell line. 876 94

Interleukin-6 (IL-6) plays a central role in the pathogenesis of multiple myeloma, acting as both a growth and a survival factor for myeloma cells. A series of IL-6 receptor antagonists that are IL-6 variants has been recently obtained, the affinity of which for the ligand-specific receptor chain IL-6R alpha has been maintained or even increased, but the signaling of which is impaired by not being able to bind and/or dimerize the signaling chain gp130. Although IL-6 antagonists have been shown to inhibit the growth of IL-6-dependent myeloma, no information has been gathered on their ability to induce myeloma cell death. We show here that IL-6 receptor antagonists are pro-apoptotic factors for the IL-6-dependent human myeloma cell line XG-1. Their capacity to induce cell death is in direct relation to their affinity for IL-6R alpha, degree of gp130 binding impairment, and efficiency to inhibit intracellular signaling events. Interestingly, the most potent pro-apoptotic molecule, Sant7, counteracts the protective autocrine effect exercised by the limited amounts of IL-6 produced by XG-1 cells and is thus able to induce cell death at higher rate than just IL-6 deprivation. These findings are particularly relevant for the therapy of multiple myeloma.
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PMID:Interleukin 6 receptor superantagonists are potent inducers of human multiple myeloma cell death. 879 94

Expression of autocrine growth factors by myeloma cells is an important mechanism that may contribute to tumor expansion. IL-6 is one of several cytokines that uses the signal transducer gp130 as a receptor component. Of these cytokines, those that have been shown to be paracrine growth factors for some myeloma cells include IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, and oncostatin M (OSM). Only IL-6, however, has been identified as an autocrine growth factor for myeloma cells. In this study we used a panel of three IL-6-responsive myeloma cell lines to investigate the expression of other autocrine growth factor loops. Initial studies employing neutralizing mAbs to IL-6 or gp130 revealed that the growth of the DP-6 and KP-6 cell lines was inhibited by both mAbs, whereas the growth of the KAS-6/1 cell line was inhibited only by the anti-gp130 mAb. Anti-OSM neutralizing mAb also inhibited KAS-6/1 cell growth. Autocrine OSM production by the KAS-6/1 cells was confirmed using a sensitive ELISA. Although the anti-OSM mAb had no significant effects on KP-6 and DP-6 cell growth, OSM was detected in DP-6 supernatants. These results suggest that OSM production and responsiveness by myeloma cells are distinct phenotypes and not necessarily related in all myeloma cells. Finally, we analyzed the significance of OSM-mediated myeloma cell growth by assessing the effects of OSM on normal, in vitro-generated plasmablasts. OSM markedly enhanced plasmablast Ig secretion but did not affect growth. Thus, the nature of the response elicited by OSM in myeloma cells is distinct from its effects on normal B lineage cells. Moreover, because gp130-mediated signaling results in myeloma cell growth, autocrine expression of any gp130-utilizing cytokine has the potential to significantly augment tumor expansion.
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PMID:Growth regulatory pathways in myeloma. Evidence for autocrine oncostatin M expression. 881 18

We have previously shown that L58 in the putative 5th helical region of human interleukin-6 (IL-6) is important for activation of the IL-6 signal transducer gp130 [de Hon et al. (1995) FEBS Lett. 369, 187-191]. To further explore the importance of individual residues in this region for gp130 activation we have now combined Ala substitutions of residues E52, S53, S54, K55, E56, L58 and E60 with other substitutions in IL-6, known to affect gp130 activation (Q160E and T163P). The combination mutant protein with L58A completely lost the capacity to induce the proliferation of XG-1 myeloma cells, and could effectively antagonize wild type IL-6 activity on these cells. Moreover, the data suggest that besides L58, S54 particularly, but also E52, S53, K55 and E56 contribute to gp130 activation.
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PMID:Identification of residues in the putative 5th helical region of human interleukin-6, important for activation of the IL-6 signal transducer, gp130. 889 3

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL-10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia-inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL-10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG-6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.
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PMID:Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. 891 64

We have previously shown that malignant plasma cells expressed the specific receptor for 1,25-dihydroxyvitamin D3 and that this derivative could significantly inhibit the proliferation of such malignant cells. More recently, new vitamin D3 derivatives have been generated with extraordinarily potent inhibitory effects on leukemic cell growth in vitro. These new data prompted us to (re)investigate the capacity of such new vitamin D3 derivatives to inhibit myeloma cell growth in comparison with that of dexamethasone, a potent antitumoral agent in multiple myeloma. In the current study, we show that EB1089, a new vitamin D3 derivative, (1) induces G1 growth arrest of human myeloma cells, which is only partially reversed by interleukin-6 (IL-6); (2) induces apoptosis in synergy with dexamethasone, IL-6, leukemia-inhibitory factor, and Oncostatin M, with an agonistic anti-gp130 monoclonal antibody being unable to prevent this apoptosis; (3) downregulates both the gp80 (ie, the alpha chain of the IL-6 receptor [IL-6Ralpha]) expression on malignant plasma cells and the production of soluble IL-6Ralpha, and finally (4) inhibits the deleterious upregulation of gp80 expression induced by dexamethasone while limiting the dexamethasone-induced upregulation of gp130 expression. Considering that these in vitro effects of EB1089 have been observed at doses obtainable in vivo (without hypercalcemic effects), our present data strongly suggest that EB1089 could have a true interest in the treatment of multiple myeloma, especially in association with dexamethasone.
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PMID:Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor modulation induced by EB1089, a vitamin D3 derivative, alone or in association with dexamethasone. 897 59


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